CERTAINLY it is possible by now to speak no longer just of T.S. Eliot's contributions to the practice and interpretation of poetry but more of his legacy to same, by which one would mean how modernist technique has permanently altered the study of poetry and therefore its very efficacy as a social and cultural medium. Indeed, thanks to the likes, in English, of poets like Eliot, Ezra Pound, and the later W.B. Yeats, we can now summarize the entire modernist movement as one that was motivated by and, in many ways, only served to further generate a crisis of meaning. Hon global that crisis was in terms of the fields of human knowing affected, let alone what its causes and other consequences were and may still continue to be, will not be the subject of the following considerations. Limiting considerations here instead to Eliot's canon alone, we find that the caliber of the poet and critic that he was challenged not merely his readers but himself as well with what has to be the ultimate epistemological question, and that is whether the meaning of any human experience, however it may be expressed, can in any way, manner, or form be satisfactorily derived from the resources of language. While this philosophical posture may be a commonplace with which we the living now happily cope, such a withering prospect had not been anywhere in view, except perhaps among the very well-closeted few--the so-called advance thinkers--before the advent of the 20th century, and the prospect most definitely found a secure locale for itself in the burgeoning of that aesthetic and critical movement called modernism, which then inoculated popularculture with the germ of an idea best kept to oneself: That nothing may mean anything, and anything may mean everything We have lost the security of certainties that we did not know we had, and replaced them with the subtleties of persistent contradicting, very much like an Eliot quatrain. So, then, the most puzzling aspects of Eliot's poetry for his contemporaries are now for us their most obvious: His questioning the meaning of meaning, both as the significance of an experience and as the significance that one can assign to experience. Philosophical idealism, according to which being is not knowing is not being, and a symbolist aesthetic, whereby all things are merely infinitely translatable signs obscuring a singularly inchoate mystery, both gripped his imaginative and intellectual instincts as a young man. His turn ultimately toward the window of the noumenal, darkened though that glass may be, in his quest for a satisfactory vision of a human life as an event that is purposefully directed makes sense therefore not as any socio-cultural strategy on his part, or as a neo-conservative reversion to traditional orthodoxies, but as one made on the basis of a personal intellectual and spiritual necessity that then, quite simply, became reflected in his poetry, a poetry which groped rather than ruminated, lurched rather than flowed. In starts and stops he sought coherence in incoherence, sense in nonsense, meaning in manner, as if the inaccessible core of understanding was a stone in his shoe, a thorn in his side, a wound in his heart. If we start and end there--with the age-old given that the poet, no matter how objectified by allusion and other public considerations the resulting compositions may seem to be, can write out of nothing more or less than his or her personal experiences--we begin and end where Eliot himself started when he famously argued for a separation between the man who suffers and the mind which creates. A separation, after all, is not a sundering; rather, it is a distillation. Whether it was Pound's images or Yeats's symbols or Eliot's allusions, they were all devices intended to serve one purpose and one purpose only, and that was to conceal personal pain and hopes and fears and feelings, beliefs, opinions, and dislikes, so that they, as poets, might not appear to be merely continuing to lament human unsuccess as all of the preceding generations of poets have only ever done. …


Importance
Burnout symptoms among physicians are common and have potentially serious ramifications for physicians and their patients. Randomized studies testing interventions to address burnout have been uncommon.

Objective
To explore the effect of individualized coaching on the well-being of physicians.

Design, Setting, and Participants
A pilot randomized clinical trial involving 88 practicing physicians in the departments of medicine, family medicine, and pediatrics who volunteered for coaching was conducted between October 9, 2017, and March 27, 2018, at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Statistical analysis was conducted from August 24, 2018, to March 25, 2019.

Interventions
A total of 6 coaching sessions facilitated by a professional coach.

Main Outcomes and Measures
Burnout, quality of life, resilience, job satisfaction, engagement, and meaning at work using established metrics. Analysis was performed on an intent-to-treat basis.

Results
Among the 88 physicians in the study (48 women and 40 men), after 6 months of professional coaching, emotional exhaustion decreased by a mean (SD) of 5.2 (8.7) points in the intervention group compared with an increase of 1.5 (7.7) points in the control group by the end of the study (P < .001). Absolute rates of high emotional exhaustion at 5 months decreased by 19.5% in the intervention group and increased by 9.8% in the control group (-29.3% [95% CI, -34.0% to -24.6%]) (P < .001). Absolute rates of overall burnout at 5 months also decreased by 17.1% in the intervention group and increased by 4.9% in the control group (-22.0% [95% CI, -25.2% to -18.7%]) (P < .001). Quality of life improved by a mean (SD) of 1.2 (2.5) points in the intervention group compared with 0.1 (1.7) points in the control group (1.1 points [95% CI, 0.04-2.1 points]) (P = .005), and resilience scores improved by a mean (SD) of 1.3 (5.2) points in the intervention group compared with 0.6 (4.0) points in the control group (0.7 points [95% CI, 0.0-3.0 points]) (P = .04). No statistically significant differences in depersonalization, job satisfaction, engagement, or meaning in work were observed.

Conclusions and Relevance
Professional coaching may be an effective way to reduce emotional exhaustion and overall burnout as well as improve quality of life and resilience for some physicians.

Trial Registration
ClinicalTrials.gov identifier: NCT03207581.


Patterns that employ sequences of distinct permutations of dancers are found in dance forms such as English country dance and contra dance, dating at least to the 1600s in England. Contemporaneously in England, the art of church bell change ringing used very similar permutation sequences. More recently, mathematicians and theoretical astrophysicists have discovered that similar patterns are stable orbits for heavenly bodies under the influence of gravity. This paper explores the connections between these art forms and recent mathematical work as well as two dances choreographed by the author that also make use of these patterns.


HIRSCHL, Ran. Constitutional Theocracy. Cambridge, MA: Harvard University Press, 2010. 306pp. Cloth, $46.50--Ran Hirschl's work addresses a question of fundamental importance for the contemporary world, the relationship between principles of the rule of law and the secular constitutional order on one hand, and religiously informed communities on the other. The book attempts to show how advocates of constitutional law and courts have emerged in many countries with established religions, serving as "bastions of relative secularism" in order to "hedge or mitigate" the influence of religiosity in the political order. Hirschl argues that the constitutionalizing of religion is itself an important step in asserting secular control over religious influences, allowing the law to restrict what is seen as the potentially dangerous excesses of religion. Hirschl commences with an overview of the rise of what he calls "constitutional theocracy" in the modern world. He defines constitutional theocracies as states that possess a clear constitutional arrangement, a religion "formally endorsed" by the state, and the "enshrining" of the religion as the main source of legislation for the state, as well as a set of religious bodies that function as important--if unofficial--transmitters of the customs and interests of the established religion. Iran is identified as perhaps the quintessential model of the "strong" form of constitutional theocracy. Chapter two provides a taxonomy of the multiple forms of constitutional orders in terms of how they might reject, accommodate, or incorporate religion. Hirschl recognizes especially the way in which some modern states have dealt with the question of religious identity. The 1937 Turkish constitution, for example, explicitly incorporated the term "secular" to describe the state (Hirschl also says "atheist," but no support is given for the claim), and Saudi Arabia, among others, has willingly suspended Shari'a principles from being applied universally, so as to accommodate modern economic practices or the tourist industry. The various reasons why secular constitutional law came to the forefront in the West, over against the claims of religious law, are analyzed in chapter three. That turn he attributes to multiple and sometimes opposing factors, including the attempt to distance religious authority from political responsibility, the desire to coopt sources of religious authority, and the view that secular courts are more reliable protectors of autonomous individual rights. Chapter four contains what might be described as the heart of the argument of the book, as Hirschl here lays out the manner in which the promotion and practice of constitutional law regularly constrains theocratic impulses in nations with large religious majorities. He treats Egypt, Pakistan, Malaysia, Israel, and Turkey at length, showing how the secular courts have routinely exercised control over the attempts by religious entities to subject the law to their "theocratic" interests. …


OBJECTIVES
To analyze our results in terms of continence and complications of treatment of urinary incontinence with TVT during the 4 first years.

METHODS
72 patients underwent surgery for urinary incontinence between 1999 and 2002. Chart review was performed for medical history, physical examination, urodynamic tests, surgical procedure, intraoperative and postoperative complications, objective and subjective results.

RESULTS
62 patients were diagnosed of genuine stress urinary incontinence and 10 patients of mixed urinary incontinence. 14 patients had grade 3 cystocele, 12 of them underwent associated colporrhaphy. Operations were performed under local anaesthesia in 1 patient, spinal anaesthesia in 41 and general anaesthesia in 30. Mean operation time was 32 minutes, 66 minutes when colporrhaphy was associated, and previous surgery did not increase the surgical difficulty. 6 patients (8.3%) suffered bladder perforation which was identified during cystoscopy, but only required reposition of the tape without affecting patients' outcomes; 1 patient had a pelvic hematoma that evolved without sequel; 16 patients (22.22%) had urinary retention which spontaneously resolved between 2 and 60 days, except one case that required section of the mesh. 8 patients (11.11%) developed de novo bladder instability; there were 2 cases of late mesh perforation into urethra or bladder, which were solved by endoscopic mesh section; 3 patients had voiding discomfort and 1 chronic perineum pain. 70 patients (97.3%) achieved continence under stress; nevertheless only 57 patients (79.17%) were satisfied with their outcomes. Main causes for dissatisfaction were failure, de novo instability, persistence of urgency in cases of mixed incontinence, and voiding discomfort. Previous surgery and performance of associated procedures did not influence outcomes, although they were associated with longer operation times and higher incidence of urinary retention. Patients with Valsalva's leak point pressure < 60 H2O cm had slightly worse outcomes (63.5% satisfaction).

CONCLUSIONS
TVT is an easy to learn and easy to perform technique, with few complications and good results.


The conceptual metaphor of 'distance' plays a crucial role in current perceptions of the world and humans' various interactions within it. It hardly seems possible to conceptualize space and time, emotional involvement in events, and relationships with other people in terms other than 'distance'. As a consequence, this primarily spatial concept figures prominently in the verbal expression of these abstract notions, and is thus highly relevant for the analysis of linguistic phenomena. In recent decades, 'distance' has been employed as a fruitful tool in different, primarily cognitive and functional, approaches. However, the explanatory power of this notion suffers from certain inconsistencies: On the one hand, very different linguistic phenomena are described in terms of 'distance', while, on the other, the notion itself relates to disparate concepts.

By providing a thorough grounding of the metaphor of distance, the present volume makes this notion tangible and thus applicable in various domains of linguistic analysis. The contributions gathered in this volume provide a concise delimitation from neighbouring concepts, and explore the rich potential of this metaphor for the analysis of the semantics, usage conditions and discourse-pragmatic effects of both morpho-syntactic categories and syntactic structures. They also investigate the role of 'distance' in understanding mechanisms of linguistic interaction. The languages covered in this volume include, amongst others, languages from the Germanic, Romance and Slavic families, as well as Japanese and Turkish.


Recently, there has been a surge of diverse approaches to investigate leaf vein patterning, covering genetic analyses, pharmacological approaches and theoretical modeling. Genetic and pharmacological approaches remain at this stage insufficient for analyzing the formation of vascular patterns since the molecular mechanisms involved are still unclear. Similarly, theoretical models are not sufficiently constrained, and thus difficult to validate or disprove. Only few exceptions attempted to provide a link between experimental and theoretical studies by implementing different imaging techniques. Visual imaging methods have been lately extensively used in applications that are targeted to understand and analyze physical biological patterns, specifically to classify different leaf species and quantify leaf venation patterns. There is a rich literature on imaging applications in the above field and various techniques have been developed. However, current methods that aimed to provide high precision results, failed to avoid manual intervention and user assistance for the developed software tools. In this paper, we introduce a fully automated imaging approach for extracting spatial vein pattern data from leaf images, such as vein densities but also vein reticulation (loops) sizes and shapes. We applied this method to quantify leaf venation patterns of the first rosette leaf of Arabidopsis thaliana throughout a series of developmental stages. In particular, we characterized the size and shape of vein network reticulations, which enlarge and get split by new veins as a leaf develops. For this purpose, the approach uses imaging techniques in a fully automatic way that enables the user to batch process a high throughput of data without any manual intervention, yet giving highly accurate results.


Course introduces students to the various ways that land is used by American Indians. We will explore traditional land use, and land issues that impact American Indians and cultural activities that are tied the land.


Exploiting the parallelism in multiprocessor systems is a major challenge in modern computer science. Multicore programming demands a change in the way we design and use fundamental data structures. The standard collection of data structures and algorithms in C++11 is the sequential standard template library (STL). In this paper, we present their vision for the theory and practice for the design and implementation of a collection of highly concurrent fundamental data structures for multiprocessor application development with associated programming interface and advanced optimization support. Specifically, the proposed approach will provide a familiar, easy-to-use, and composable interface, similar to that of C++ STL. Each container type will be enhanced with internal support for nonblocking synchronization of its data access, thereby providing better safety and performance than traditional blocking synchronization by: 1) eliminating hazards such as deadlock, livelock, and priority inversion and 2) by being highly scalable in supporting large numbers of threads. The new library, lockless containers/data concurrency, will provide algorithms for handling fundamental computations in multithreaded contexts, and will incorporate these into libraries with familiar look and feel. The proposed approach will provide an immense boost in performance and software reuse, consequently productivity, for developers of scientific and systems applications, which are predominantly in C/C++. STL is widely used and a concurrent replacement library will have an immediate practical relevance and a significant impact on a variety of parallel programming domains including simulation, massive data mining, computational biology, financial engineering, and embedded control systems. As a proof-of-concept, this paper discusses the first design and implementation of a wait-free hash table.


Environmental subsidy for infrastructure projects is an effective way to solve the current worsening of the environment. To examine how subsidy affects investors to entry and exit the environmental infrastructure projects is a prerequisite for the decision of environmental policy. Different from the existing literature, the option game theory is applied to construct a symmetric duopoly model of investment with entry and exit decisions under uncertainty in this paper. As a result, the relation between entry and exit optimal thresholds and subsidies is shown. Moreover, the equilibrium strategies corresponding subsidies are given.


A new text categorization problem is introduced. As in the classical problem, there is a set of documents and a set of categories. However, in addition to being assigned to a specific category, each document belongs to a certain sequence of documents, referred to as a case. It is assumed that all documents in the same case belong to the same category. An example may be a set of news articles. Their categories may be sport, politics, entertainment, etc. In each category there exist cases, i.e., sequences of documents describing, for example evolution of some events. The problem considered is how to classify a document to a proper category and a proper case within this category. In the paper we formalize the problem and discuss two approaches to its solution.


The part of the tourism industry which covers events, conventions and meetings is a substantial part of the global economy and provides employment for a very large number of people worldwide. The breakdown of employees in this sector is complex - employees can be full-time, casual labour or part of a volunteer workforce, and events can be as diverse as the Olympic Games and a local meeting. This book examines the role of people who work in events, meetings and conventions by looking at the context in which they work, and presenting theories, perspectives underlying trends of employment in this sector. Leading authors present international examples to further understanding of the concepts involved in people management in tourism events. This book will be an important resource for students and researchers of leisure, tourism and events management.


Given the explosive growth of the Web and the popularity of image sharing Web sites, image retrieval plays an increasingly important role in our daily lives. Search engines aim to provide beneficial image search results to users in response to queries. The quality of image search results depends on many factors: chosen search algorithms, ranking functions, indexing features, the base image database, etc. Applying different settings for these factors generates search result lists with varying levels of quality. Previous research has shown that no setting can always perform optimally for all queries. Therefore, given a set of search result lists generated by different settings, it is crucial to automatically determine which result list is the best in order to present it to users. This paper proposes a novel method to automatically identify the best search result list from a number of candidates. There are three main innovations in this paper. First, we propose a preference learning model to quantitatively study the best image search result identification problem. Second, we propose a set of valuable preference learning related features by exploring the visual characters of returned images. Third, our method shows promising potential in applications such as reranking ability assessment and optimal search engine selection. Experiments on two image search datasets show that our method achieves about 80% prediction accuracy for reranking ability assessment, and selects optimal search engine for about 70% queries correctly.


Introduction, definition, rationale and scope: Lasers are now becoming an integral part of dermatological practice in India, with more and more dermatologists starting laser dermatology practice. Lasers, when are used with care, by properly trained operators, in carefully designed environment, can deliver a range of useful aesthetic and dermatologic treatments. Facility: Laser treatment is an office procedure, hence it does not require hospital set-up. The laser room facility requires careful planning keeping in mind safety of both patient and operator, convenience of operating, and optimum handling of costly equipments. The facility should be designed to handle procedures under local anesthesia and sedation. Facilities, staff and equipment to handle any emergencies should be available. Location: A room in existing dermatology clinic can be adequately converted to a laser room. Dimensions of laser room, its door and patient's table should be such that it should facilitate easy movement of patient, machine trolley, operator and assistant in case of routine procedures and in emergency. Physician Qualification: Any dermatologist with MD or diploma in dermatology can do laser procedures, provided he/ she has acquired necessary skills by virtue of training, observing a competent dermatologist. Such training may be obtained during post graduation or later in specified workshops or courses under a competent dermatologist or at centre which routinely performs such procedures. Electricity and uninterrupted power supply: Laser equipments should be connected to stabilizer or UPS circuits only. Preferably an on line UPS as recommended by the laser company should be installed. Earthing of the equipment is essential to avoid damage to the equipment and electrical shocks to the operator. Sufficient power back up to complete the procedure if power is off midway, is essential. Air-conditioning: Laser machines should be operated in low ambient temperature, with low humidity and dust free environment for longer life of machines. Patient chair: A dental/cosmetic chair with adjustable task light is a suitable option for patient positioning. The chair should have the option to tilt head down or 'syncope position' to facilitate resuscitation of a patient in vaso-vagal shock. Maintenance: Annual maintenance contract (AMC) is essential after warranty period is over and is essential for insurance purposes. Mobile Laser Unit: Mobile laser units are of relevance in the Indian context to render laser facility available in smaller towns. A laser with fiber optic delivery system can be made mobile after consultation with supplier. However a laser with an articulated arm delivery cannot be made mobile. Proper packing with shock absorbing material is necessary during transportation. The area where lasers are to be moved to and operated should have appropriate facilities as mentioned above. Records: Patient's health declaration questionnaires, laser register are essential records. Digital photography before and at regular intervals after procedure is an essential record. Detailed informed consent in patients language for each procedure explaining nature of procedure, anesthesia used, and machine used, post operative down time should be signed by patient. Drugs, anesthesia and sterilization: An electrocautery machine to control bleeding, equipments for airway maintenance, other instruments for emergency resuscitation and an emergency drug tray are essential. Standard sterilization practices are adopted. For most of laser procedures topical anesthesia is sufficient. Safe laser use: Protocols of safe laser use to avoid burns or eye damage to patients or operator are adopted. Reflective surfaces like mirrors, reflective jewelleries are not allowed in laser room. Machine should always be on standby mode when not in direct use. It should be used by authorized operator only. Eye protection: Goggles of sufficient optical density (OD) intended to protect from specific laser wavelength are to be used by all persons in laser room. Patient is given either same goggle or laser opaque shield. For procedures around eyes or on eyelids, internal eye shield made of laser opaque material are to be used. Fire extinguisher complying with local authority fire rules should be available and staff should be trained to use that. Safety and emergency protocols: Protocols for certain situations like vasovagal attack, anaphylaxis, uncontrolled bleeding, fire, accidental eye exposure should be in place and staff should be trained for these situations.


We determine the spaces of states of the two-dimensional O(n)O(n) and QQ-state Potts models with generic parameters n,Q\in \mathbb{C}n,Q∈ℂ as representations of their known symmetry algebras. While the relevant representations of the conformal algebra were recently worked out, it remained to determine the action of the global symmetry groups: the orthogonal group for the O(n)O(n) model, and the symmetric group S_QSQ for the QQ-state Potts model. We do this by two independent methods. First we compute the twisted torus partition functions of the models at criticality. The twist in question is the insertion of a group element along one cycle of the torus: this breaks modular invariance, but allows the partition function to have a unique decomposition into characters of irreducible representations of the global symmetry group. Our second method reduces the problem to determining branching rules of certain diagram algebras. For the O(n)O(n) model, we decompose representations of the Brauer algebra into representations of its unoriented Jones-Temperley-Lieb subalgebra. For the QQ-state Potts model, we decompose representations of the partition algebra into representations of the appropriate subalgebra. We find explicit expressions for these decompositions as sums over certain sets of diagrams, and over standard Young tableaux. We check that both methods agree in many cases. Moreover, our spaces of states are consistent with recent bootstrap results on four-point functions of the corresponding CFTs.


The healthcare system of almost all industrialized countries has improved during the last decades which results in lengthen life expectancy. But from this circumstances arises an increasing number of patients with a chronic disease. The e-health system was developed as a cost-effective response to this problem. Though there are still several issues with e-health and the superiority of web-based interventions against non-web-based interventions has not been proven, either. In this thesis the question is examined how satisfied e-health users are with the offered care. In order to answer this question a systematic review was performed. Different search terms were insert into four different bibliographical databases which results in 3761 articles at the beginning. At basis of these titles the number of articles could be reduced to 749. By the selection of abstracts the number of articles was reduced to 118 once again. At the end of this process there were 10 articles which were screened on full-text. Additionally to this full-text screening an efficacy analysis with regard to satisfaction of the users was performed. 7 interventions are considered as effectively leading to satisfaction, 3 interventions rank as not effective. The analyses of satisfaction shows that especially the interventions with features like 'logistic', 'practicing' en 'drawing up aims' are considered as satisfying. Moreover there is an increased appearance of the features 'education' and 'monitoring' in interventions which are not effective with regard to satisfaction of users. Users named further 'information with directly appearing feedback', 'a good communication with the nurse' and 'intense exercises' as causes of satisfaction with the intervention
The analysis proofed that the typically user of web-based interventions is satisfied with the offered care, but it was also obvious that this degree of satisfaction is overrated. Methodological failures and differences in quality of the interventions affect the results. Users are not satisfied with every part of the interventions either. Also were certain features estimated as more satisfying than others. It is advisable that there is further research within this topic to get an overview of the satisfaction of e-health user and factors that influence this satisfaction. Thereby, one important question is why certain features were perceived as more satisfying than others and how these features influence satisfaction.


Statistical and dynamic methods were used in the downscaling process from Global Climate Model (GCM) to Regional Climate Model (RCM). We selected the European Centre for Medium-Range Weather Forecasts model, Hamburg version 4 (ECHAM4) with 300 × 300 km resolution for A2 scenario. We focused on SE Asia domain located between 20°S to 30°N and 80°E to 135°E for 1960– 2099 with wind components, temperature, geo-potential height, and specific humidity as data input in Providing Regional Climates for Impacts Studies (PRECIS) RCM analysis. The downscaling process output was 50 km resolution for 1971–2010 and precipitation, temperature, wind, relative humidity, radiation from 8 meteorological stations in Chao Phaya River Basin; Lampang, Suphanburi, Nan, Sisamrong, Takfa, Chainat, Uthong and Bangna selected and used for bias correction. Three methods, namely 1) adjusting the mean based on RCM, 2) adjusting the mean based on observation, and 3) quantile-based mapping were used. Methods were compared using observed climatic data, RCM outputs of calibration period, and RCM outputs from the validation period. RSME was found to be lower for method 2 compared to other methods implying a relatively superior technique for improving the model. As such method 2 was used to correct the PRECIS products during 2001– 2009. These products are useful in the studies of impact of climate change and for early warning systems in Thailand.


Recent advances in Artificial Intelligence (AI) have revived the quest for agents able to acquire an open-ended repertoire of skills. However, although this ability is fundamentally related to the characteristics of human intelligence, research in this field rarely considers the processes that may have guided the emergence of complex cognitive capacities during the evolution of the species.
Research in Human Behavioral Ecology (HBE) seeks to understand how the behaviors characterizing human nature can be conceived as adaptive responses to major changes in the structure of our ecological niche. In this paper, we propose a framework highlighting the role of environmental complexity in open-ended skill acquisition, grounded in major hypotheses from HBE and recent contributions in Reinforcement learning (RL). We use this framework to highlight fundamental links between the two disciplines, as well as to identify feedback loops that bootstrap ecological complexity and create promising research directions for AI researchers.


Abstract. Conventional techniques to measure boundary layer clouds such as research aircraft are unable to sample in orographically diverse or densely populated areas. In this paper, we present a newly developed measurement platform on a tethered balloon system (HoloBalloon) to measure in situ vertical profiles of microphysical and meteorological cloud properties up to 1 km above ground. The main component of the HoloBalloon platform is a holographic imager, which uses digital in-line holography to image an ensemble of cloud particles in the size range from small cloud droplets to precipitation-sized particles in a three-dimensional volume. Based on a set of two-dimensional images, information about the phase-resolved particle size distribution, shape and spatial distribution can be obtained. The velocity-independent sample volume makes holographic imagers particularly well suited for measurements on a balloon. The unique combination of holography and balloon-borne measurements allows for observations with high spatial resolution, covering cloud structures from the kilometer down to the millimeter scale. The potential of the measurement technique in studying boundary layer clouds is demonstrated on the basis of a case study. We present observations of a supercooled low stratus cloud during a Bise situation over the Swiss Plateau in February 2018. In situ microphysical profiles up to 700 m altitude above the ground were performed at temperatures down to −8 ∘C and wind speeds up to 15 m s−1. We were able to capture unique microphysical signatures in stratus clouds, in the form of inhomogeneities in the cloud droplet number concentration and in cloud droplet size, from the kilometer down to the meter scale.


BACKGROUND
Previous studies show that prazosin, an α(1) -adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence [Rasmussen et al. (2009) Alcohol Clin Exp Res 3:264-272; Walker et al. (2008) Alcohol 42:91-97] and in alcohol-dependent men [Simpson et al. (2009) Alcohol Clin Exp Res 33:255-263]. This study extended these findings by using a paradigm that allows for separate assessment of prazosin on motivation to seek versus consume alcohol or sucrose in selectively bred rats.

METHODS
Alcohol-preferring (P) rats were trained to complete an operant response that resulted in access to either 2% sucrose or 10% alcohol. A 4-week Seeking Test Phase examined responding in single, weekly extinction sessions when no reinforcer could be obtained. A 4-week Drinking Test Phase consisted of rats lever-pressing to "pay" a specified amount up front to gain access to unlimited alcohol (or sucrose) for a 20-minute period. On Seeking and Drinking test days, prazosin (0.0, 0.5, 1.0, and 1.5 mg/kg) was administered intraperitoneally 30 minutes prior to behavioral sessions.

RESULTS
Rats were self-administering an average of 0.9 (±0.09) g/kg alcohol on vehicle test day and had pharmacologically relevant blood ethanol concentrations. Prazosin significantly decreased alcohol seeking at all doses tested. The highest dose of prazosin also increased the latency to first response for alcohol and decreased alcohol intake. While sucrose-seeking and intake were similarly affected by prazosin, the high dose of prazosin did not increase response latency.

CONCLUSIONS
These findings are consistent with and extend previous research and suggest that prazosin decreases motivation to initiate and engage in alcohol consumption. The specificity of prazosin in attenuating the initiation of alcohol- but not sucrose-seeking suggests that this effect is not because of prazosin-induced motor-impairment or malaise. Together with previous findings, these data suggest that prazosin may be an effective pharmacotherapy, with specific application in people that drink excessively or have a genetic predisposition to alcohol abuse.


Drinks giant Diageo is funding a training scheme that aims to teach midwives to advise expectant mothers of the risks of drinking alcohol during pregnancy.

The scheme, run by the National Organisation for Foetal Alcohol Syndrome (NOFAS-UK), hopes to reach 10 000 midwives and one million pregnant women over five years.

In its second year the project has already trained 800 midwives with funding from Diageo, producer of brands including Guinness, Johnnie Walker, and Smirnoff. The scheme is part of the government's drive to increase private investment in public health initiatives.

The advice given by the NOFAS differs from the Department of Health's. The organisation advises women to abstain entirely from alcohol during pregnancy and while trying to conceive, whereas the Department of Health says that, although women should avoid alcohol during pregnancy, "if they do choose to drink, to minimise the risk to the baby, they should not drink more than 1 or 2 …


Invinsa blocks ethylene perception by plants and can reduce the negative effects of water stress on crop growth. The objective of this study is to measure the effect on corn growth and yield of Invinsa application at incipient water stress. A study was conducted at the University of Arizona Maricopa Agricultural Center where Invinsa was applied on 15 May in blocks with adequate or deficit irrigation. The deficit irrigation block received no irrigation water for 7 days past incipient stress beginning on 15 May, but otherwise received adequate water during the other parts of the season. Invinsa had little or no effect on crop growth measured at five different dates during the growing season. Invinsa had no effect on grain yield, grain moisture content, harvest index, ear number, kernels per ear, kernel weight, and silking date. We were not able to measure an effect of Invinsa on photosynthetic rate, conductance to water, intercellular CO2 concentration, vapor pressure deficit, or leaf temperature. However, Invinsa increased daily water use at various time periods, particularly in the adequate irrigation regime. The lack of a response this year to Invinsa, other than water use, is similar to the results from last year where no consistent response was measured. Invinsa has increased corn yield in other regions, and heat and/or water stress at the Maricopa may mask the effects of Invinsa or render it ineffective.


In order to understand the geology of the country north of the Aire, I will first give a short sketch of the chief features presented by the Millstone Grit and Lower Carboniferous measures, as we follow the beds from Derbyshire to Wensleydale.

In Derbyshire the Millstone Grit, as hitherto defined, consists in descending order of four or five well-marked grits, separated by shales, viz., the so-called first or topmost grit, named also Rough rock from its coarse character; the second grit, generally a flagstone; the bold, well-jointed rock of Hathersage Edge and Stanedge, or the third grit; and lastly, the fourth or Kinderscout grit, which sometimes consists of two beds.

Below the Kinderscout grit comes a thick and variable series of sandstones and sandy shales, the " shale grit" of Farey, which has been generally called the Yoredale or Upper Yoredale grit; and then come shales in which sometimes occur siliceous sandstones, known as Yoredale Sandstones, or Lower Yoredale Grit; then come calcareous shales; and finally the Carboniferous Limestone of unknown thickness, the upper part of which is thin-bedded and cherty, the lower massive and free from chert.

Going northwards this type undergoes great changes; the second grit is merely a basement bed to the Rough Rock, from which it cannot always be separated; the third grit loses its massive character in many places; and other beds of sandstone show themselves amid the shales overlying the Kinderscout grit.

In the valley of the Colne there are four sandstones between the ...


PurposeThis paper explores the challenge of "fuzzy" assessment criteria and feedback with a view to aiding student learning. The paper untangles three guiding principles as mechanisms to enhance the effectiveness of assessment and feedback through overcoming the inherent challenges which stem from tacit judgement during assessment.Design/methodology/approachThe paper applies a realistic evaluation methodology, with a framework for assessment and feedback consisting of three principles – Means, Opportunity and Motivation (MOM). Through in-depth interviews with undergraduate and postgraduate management students the paper identifies how and when the means, opportunity and motivation principles impact student learning through assessment and the utility of the feedback received on their learning.FindingsThe findings in the paper illustrate that students do not always understand the feedback they receive on their learning because they do not fully understand the criteria to which it refers due to the tacit dimensions of assessment. The findings substantiate the proposition that effective assessment processes must ensure that students have the means, opportunity and motivation to use feedback and to understand the criteria, a central component of which is understanding tacit dimensions of assessment.Practical implicationsThe paper deciphers three practical implications for instructors related to (1) teaching, (2) course and program design and (3) the nature of the feedback instructors should provide.Originality/valueWhile prior scholarship has flagged the challenge of "fuzzy" assessment and feedback, this paper identifies when and how the means, opportunity and motivation principles are manifested in the process of making the tacit components of assessment codified and actionable, a critical process in developing expert learners.


The standard algorithm for computing the soft-inverse of a finite-state machine (i.e., the soft-in/soft-out or SISO) module, is the forward-backward algorithm. These forward and backward recursions can be computed in parallel, yielding an architecture with latency /spl Oscr/(N), where N is the block size. We demonstrate that the standard SISO computation may be formulated. Using a combination of a prefix and suffix operations. Based on well-known tree-structures for fast parallel prefix computations in the very large scale integration literature (e.g., tree adders), we propose a tree-structured SISO that has latency /spl Oscr/(log/sub 2/N). The decrease in latency comes primarily at a cost of area, with, in some cases, only a marginal increase in computation. We discuss how this structure could be used to design a very high throughput turbo decoder, or more generally an iterative detector. Various sub-windowing and tiling schemes are also consider to further improve latency.


Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC

Introduction: Pilocytic astrocytoma (PA) is the most common childhood brain tumor. This tumor can occur throughout the central nervous system, with roughly 50% of cases arising outside of the cerebellum. Tumors in these non-cerebellar locations are often difficult to treat surgically, leading to multiple tumor recurrences. PA can therefore become a chronic disease, with patients experiencing substantial morbidities. Alterations in the MAPK pathway, particularly BRAF, have previously been identified in ∼80% of PAs. Interestingly, however, the majority of those cases without a recognized change are non-cerebellar.

Methods: To investigate the full range of genetic alterations occurring in PA, we used Illumina HiSeq technologies to perform whole-genome sequencing of matched tumor and germline DNA from 47 patients, with corresponding RNA sequencing data for 35 tumors.

Results: The average somatic mutation rate in PA was extremely low, at 0.065/Mb, with an average of only 1.8 non-synonymous coding single nucleotide variants (SNVs) per tumor - almost ten times lower than we have recently reported for medulloblastoma. We found several novel alterations in known PA-related genes, including two new oncogenic BRAF fusions. Most strikingly, however, we identified mutations at two hotspots in the FGFR1 receptor tyrosine kinase in 4/6 centrally located PAs lacking any other MAPK pathway change. Two of these cases also carried a mutation in a downstream adaptor protein, PTPN11 (Shp2). Interestingly, germline mutations of PTPN11 are associated with Noonan syndrome (NS), and there are case reports of NS patients developing PAs. Screening of additional non-cerebellar PAs revealed four further cases with an FGFR1 mutation. All PAs, regardless of MAPK pathway alteration, displayed highly elevated expression of FGF2, indicating a general role for ligand-mediated activation of the FGFR1/MAPK pathway in PA tumorigenesis. Notably, the same FGFR1 mutations were also identified in four midline pediatric glioblastomas (GBM), a highly malignant brain tumor, suggesting a possible common origin for a subset of these two entities, despite their dramatically different clinical course.

Conclusion: Altogether, MAPK alterations were identified in 96% of PAs, with very few other changes, confirming the concept of PA as a single-pathway disease. Our results also suggest that a subset of centrally located, FGFR1-driven pediatric PAs and GBMs may share common origins. Most importantly, they reveal a novel therapeutic target in clinically relevant subsets of childhood glioma.

Citation Format: David TW Jones, Barbara Hutter, Natalie Jager, Andrey Korshunov, Marcel Kool, Sally R. Lambert, Dong Anh Khuong Quang, Adam M. Fontebasso, Marina Ryzhova, Hans-Jorg Warnatz, Thomas Zichner, Jan O. Korbel, Stephan Wolf, Marie-Laure Yaspo, Keith L. Ligon, Mark W. Kieran, Benedikt Brors, Jorg Felsberg, Guido Reifenberger, V. Peter Collins, Nada Jabado, Roland Eils, Peter Lichter, Stefan M. Pfister, ICGC PedBrain Tumor Project. Recurrent FGFR1 hotspot mutations represent a novel therapeutic target in childhood astrocytoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4594. doi:10.1158/1538-7445.AM2013-4594


Lead magnesium niobate-lead titanate (0.8Pb(Mg1/3Nb2/3)O3-0.2PbTiO3, PMN-PT) thick films in the thickness range about 75 μm have been successfully fabricated on Au-coated Al2O3 substrates by electrophoretic deposition (EPD). Non-aqueous colloidal suspensions suitable for EPD were prepared by mixing ultrasonically PMN-PT particles in ethanol with pH=6.0. The effect of EPD process parameters such as deposition voltage, deposition time and the specific deposition mass of PMN-PT particles were investigated. The EPD parameters were optimized in order to obtain crack-free, high-quality uniform ceramic films. The deposited pyrochlore-free PMN-PT thick films were sintered at 1000oC for 30 min, and the phase evolvement and the microstructure of the film were characterized by X-ray diffraction and scanning electron microscope.


First announced in 2013, the Belt and Road Initiative (BRI) has become a central component of Chinese foreign policy under the presidency of Xi Jinping. Given the scope and vision of the BRI, several fundamental questions have been raised by the policy. Is the BRI threatening? Will it strengthen the system? Will it supplement it? In order to explore this puzzle, the thesis undertakes empirical analyses of the BRI and the accompanying Asian Infrastructure Investment Bank (AIIB). These analyses will be placed within a container of the Liberal International Order (LIO). This framework, derived from the writings of G. John Ikenberry, is based around four elements: Open Multilateral Trade, International Institutions, Liberal Democracy and Neoliberal World Economy. The findings show that the BRI and AIIB have combined to create a disorientating picture in which elements of the LIO are both strengthened and undermined. This allows China to sit benignly within the order while constructing the infrastructure needed to break from the system - if and when required.


Heterozygous germline mutations in the gene encoding type II bone morphogenetic protein receptor (BMPRII) underlie the majority (~80%) of the familial form of pulmonary arterial hypertension (HPAH).1 PAH is a devastating cardiovascular disorder caused by narrowing of blood vessels in the lungs. We earlier demonstrated that mutations in BMPR2 impinge upon the BMP signalling pathway and potentiate the TGF-β² signalling leading to abnormal proliferation and apoptosis resistance of endothelial and pulmonary arterial smooth muscle cells (PASMCs).2,3 No cure for this disorder is known. Traditional therapies aim to improve cardiopulmonary function and were established before recognising the involvement of substantial genetic components of PAH. Hence, there is an urgent need to identify novel compounds capable of providing therapeutic intervention prior to or following the onset of disease. High-throughput cell based BMP-responsive screens were carried out, which identified several natural compounds as hits. The hit compounds were optimised through a medicinal chemistry programme. These compounds were tested in a number of cell based experiments including reporter assays, gene expression studies and western blot analyses. The compounds CRT-01, CRT-02 and CRT-03 enhanced BMP signalling in BMP responsive reporter assays. Moreover, these compounds were able to induce BMP responsive id1 gene expression and increased the phosphorylation of SMAD1/5 proteins. Furthermore, these compounds inhibited excessive proliferation of PASMCs harbouring a pathogenic BMPR2 mutation. Taken together, this study identified novel compounds eliciting pro-BMP effects which may have experimental and clinical applications in PAH. References Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nature genetics2000;26(1):81–84. Nasim MT. Ghouri A, Patel B, James V, Rudarakanchana N, Morrell NW, Trembath RC.Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet2008;17(11);1683–94. Nasim MT, Ogo T, Chowdhury HM, Zhao L, Chen CN, Rhodes C, Trembath RC. BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH.Hum Mol Genet2012;21(11):2548–58.


Multilevel models are often used to account for the hierarchical structure of social data and the inherent dependencies to produce estimates of regression coefficients, variance components associated with each level, and accurate standard errors. Social network analysis is another important approach to analysing complex data that incoproate the social relationships between a number of individuals. Extended linear regression models, such as network autoregressive models, have been proposed that include the social network information to account for the dependencies between persons. In this article, we propose three types of models that account for both the multilevel structure and the social network structure together, leading to network autoregressive multilevel models. We investigate theoretically and empirically, using simulated data and a data set from the Dutch Social Behavior study, the effect of omitting the levels and the social network on the estimates of the regression coefficients, variance components, network autocorrelation parameter, and standard errors.


We report the effect of glutathione and the role of reactive oxygen species (ROS), assayed by a nitro blue tetrazolium reaction, on the antibacterial action of ciprofloxacin, gentamicin and chloramphenicol in Staphylococcus aureus 22 resistant to ciprofloxacin and gentamicin, and in S. aureus ATCC 29213 sensitive to the above three antibiotics. The association of glutathione with ciprofloxacin or gentamicin significantly reduced the value of the minimum inhibitory concentration (MIC) in resistant S. aureus 22, measured using the macrodilution method, with a concomitant increase of intracellular ROS and a decrease of extracellular ROS. However, glutathione did not induce modifications in MIC or ROS generated by chloramphenicol. Furthermore, in the sensitive S. aureus ATCC 29213, the association of glutathione with ciprofloxacin, gentamicin or chloramphenicol did not induce any significant variations of MIC or ROS. There was a correlation between the stimulus of intracellular ROS and the decrease of MIC caused by exogenous glutathione. According to the results obtained, it is possible to modify the sensitivity of resistant strains of S. aureus by the addition of exogenous glutathione.


Background & Aim: Mechanical ventilation after open-heart surgery is one of the essential practices in patients. Awareness about some variables which are associated with extubation time; is necessary for decision making about the appropriate time for this procedure. The purpose of this study was to determine whether sex, age and postoperative homodynamic status are associated with extubation time after Coronary Artery Bipass Graft (CABG). Material & Method: The research was conducted in a university-affiliated hospital in Tehran. In this cross-sectional study, data were collected by reviewing of 93 records of eligible patients by convenience sampling method. Data collecting tool was a checklist and data analyzed by chi-square and regression analysis. Results: Fourty three percent of patients were extubated in 6 hours or less and 57% of them were extubated in more than 6 hours after surgery. The mean of intubation time was 7.19±3.00 hours, with a range of 3.00-18.25 hours. Age was the only variable that was found to be statistically significant to extubation time (P<0.05). Conclusion: According to the findings, age is associated with intubation time after CABG. Therefore, nurses should take into the account this factor to make decision regarding the time of extubation in older patients.


The purpose of this paper is to obtain relevant data on materials that are the most commonly used in fuel-cell and hydrogen technologies. The focus is on polymer-electrolyte-membrane fuel cells, solid-oxide fuel cells, polymer-electrolyte-membrane water electrolysers and alkaline water electrolysers. An innovative, methodological approach was developed for a preliminary material assessment of the four technologies. This methodological approach leads to a more rapid identification of the most influential or critical materials that substantially increase the environmental impact of fuel-cell and hydrogen technologies. The approach also assisted in amassing the life-cycle inventories—the emphasis here is on the solid-oxide fuel-cell technology because it is still in its early development stage and thus has a deficient materials' database—that were used in a life-cycle assessment for an in-depth material-criticality analysis. All the listed materials—that either are or could potentially be used in these technologies—were analysed to give important information for the fuel-cell and hydrogen industries, the recycling industry, the hydrogen economy, as well as policymakers. The main conclusion from the life-cycle assessment is that the polymer-electrolyte-membrane water electrolysers have the highest environmental impacts; lower impacts are seen in polymer-electrolyte-membrane fuel cells and solid-oxide fuel cells, while the lowest impacts are observed in alkaline water electrolysers. The results of the material assessment are presented together for all the considered materials, but also separately for each observed technology.


The spectrum and the importance of imported diseases are different in immigrants than in tourists returning from their vacations in the tropics. Infectious diseases may take another course, specific genetic diseases such as hemoglobin related diseases play an important role. Tuberculosis, intestinal verminosis, schistosomiasis, and malaria are frequently imported infectious diseases. The tuberculosis is of significance because of its frequency, risk of infection, and because of the increasing resistance to the Mycobacterium tuberculosis. The schistosomiasis may have no symptoms over a long period but may cause dangerous illness later on. One should think of the malaria in any case of unclear fever. On the other hand, immigrants may have a parasitemia with Plasmodium falciparum without having symptoms. This may be of importance in blood transfusions. The experience of physical illness and its description as well as the tolerance to treatment procedures may differ from culture to culture.


Factor D (D) is an essential component of the alternative complement pathway. To determine whether D is catabolized by the kidney and, if so, at what site, we studied the renal handling of human D by in vivo nephron microperfusion and in vitro perfusion of rat kidneys. Human D was purified and labeled with 125I. Individual nephrons were perfused in vivo at varying rates with perfusate that contained 125I-D and [14C]inulin. When nephrons were perfused from proximal sites with perfusate 125I-D in a concentration of 3.0 micrograms/ml, urinary recovery of 125I-D increased (P less than 0.05) from 57.7 +/- 5.0 to 74.4 +/- 2.5% as tubule fluid flow rate was increased from 10 to 40 nl/min; recovery of 125I-D was less than (P less than 0.001) [14C]inulin recovery at all perfusion rates. At 20 nl/min, an increase in perfusate 125I-D concentration from 1.5 to 3.0 micrograms/ml was associated with an increase (P less than 0.001) in urinary 125I-D recovery (42.1 +/- 4.0 vs. 65.8 +/- 2.6%). Similarly, the addition of unlabeled D, 30 micrograms/ml, to 125I-D, 3.0 micrograms/ml, increased urinary 125I-D recovery (95.3 +/- 2.1%) at 20 nl/min. When nephrons were perfused from early distal segments at 10 nl/min, 125I-D recovery (91.2 +/- 4.3%) did not differ from [14C]inulin recovery (95.8 +/- 1.3%). In the isolated perfused filtering kidney, the concentration of intact 125I-D in the perfusate declined 60.3 +/- 14.6% over 1 h. 83.4 +/- 6.3% of the decrement in 125I-D was catabolized by the kidney; the remainder was excreted in the urine as intact D. When glomerular filtration was prevented by increasing perfusate albumin concentration to 16 g/dl, perfusate intact (125I-D) remained unchanged over 1 h. These data show that human D is catabolized by the kidney via glomerular filtration and reabsorption by the proximal nephron. Reabsorption of D appears to be a saturable process.


ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 cell-to-cell transmission is dependent on the release of infectious virus particles into the virological synapse. The HTLV-1 particle structure is still poorly understood, and previous studies analyzed viruses produced by transformed lymphocytic cell lines chronically infected with HTLV-1, particularly the MT-2 cell line, which harbors truncated proviruses and expresses aberrant forms of the Gag protein. In this study, we demonstrate that the chronically infected SP cell line harbors a relatively low number of proviruses, making it a more promising experimental system for the study of the HTLV-1 particle structure. We first identified the genomic sites of integration and characterized the genetic structure of the gag region in each provirus. We also determined that despite encoding a truncated Gag protein, only the full-length Gag protein was incorporated into virus particles. Cryo-transmission electron microscopy analyses of the purified virus particles revealed three classes of particles based upon capsid core morphology: complete cores, incomplete cores, and particles without distinct electron densities that would correlate with the capsid region of a core structure. Observed cores were generally polygonal, and virus particles were on average 115 nm in diameter. These data corroborate particle morphologies previously observed for MT-2 cells and provide evidence that the known poor infectivity of HTLV-1 particles may correlate with HTLV-1 particle populations containing few virus particles possessing a complete capsid core structure. IMPORTANCE Studies of retroviral particle core morphology have demonstrated a correlation between capsid core stability and the relative infectivity of the virus. In this study, we used cryo-transmission electron microscopy to demonstrate that HTLV-1 particles produced from a distinct chronically infected cell line are polymorphic in nature, with many particles lacking organized electron densities that would correlate with a complete core structure. These findings have important implications for infectious HTLV-1 spread, particularly in the context of cell-to-cell transmission, a critical step in HTLV-1 transmission and pathogenesis.


A study was undertaken to determine the ability of the DNA hypomethylating drug 5-aza-2'-deoxycytidine (5-azadCyd) to induce antigen expression in a high proportion of treated tumor cells and to evaluate if this effect could be mimicked by the drug hydroxyurea (HU) which is a genomic DNA hypermethylating agent. Induction of heritable changes in gene expression by 5-azacytidine or the 2'-deoxy analogue (5-azadCyd), at least in some cases, may not be necessarily due to their hypomethylating properties, but to some other induced high frequency genetic change which occurs when DNA synthesis or repair is perturbed. A comparison of 5-azadCyd and HU effects on human and murine tumors was chosen for this study. The phenotypic properties examined with the above treatments were (a) induction of a Mr 110,000 antigen, detected with M111 antibody, in a variant subpopulation (SMeLus7) of human melanoma cells which fail to maximally express this antigen (M111). The parent cell line, MeWo, and other MeWo-derived variant cell cell lines do not demonstrate a similarly inducible phenotype; and (b) induction of class I major histocompatibility complex antigens in a population of mouse mammary adenocarcinoma cells which normally fail to express these antigens. The results showed that 5-azadCyd was effective in inducing antigen expression in both systems whereas HU was effective (and equally so) only in the human melanoma cell line system. In these treatments 5-azadCyd was demonstrated to transiently hypomethylate the same human melanoma cell line whereas HU hypermethylated genomic cytosines. The results suggest that some of the reported effects of 5-azacytidine or 5-azadCyd in inducing very high frequency heritable phenotypic alterations may not necessarily be related to the drugs' ability to cause DNA hypomethylation. The implications of these results are discussed in terms of the use of 5-azacytidine or 5-azadCyd and the effects of chemotherapy on tumor progression and metastasis.


This paper describes in detail the design of a CMOS custom fast Fourier transform (FFT) processor for computing a 256-point complex FFT. The FFT is well-suited for real-time spectrum analysis in instrumentation and measurement applications. The FFT butterfly processor reported here consists of one parallel-parallel multiplier and two adders. It is capable of computing one butterfly computation every 100 ns thus it can compute a 256-point complex FFT in 102.4 /spl mu/s excluding data input and output processes.


Caesarean scar ectopic pregnancy (CSEP) is one of the rarest forms of ectopic pregnancy. It is characterised by a gestation implanted in a caesarean section scar and surrounded by the myometrium and the fibrous tissue of the scar. With rising caesarean delivery rates and widespread use of ultrasound in early pregnancy, there is a parallel upward trend in the incidence of CSEP. The most significant risk associated with a CSEP is an early uterine rupture with life-threatening maternal haemorrhage leading to hysterectomy and loss of reproductive potential. An early diagnosis can offer conservative treatment options capable of preserving the uterus. This chapter discusses the clinical presentation, diagnosis and evidence-based treatment options of CSEP.


Background The potential legalisation of physician assisted suicide (PAS) in the UK has become a hotly debated issue in recent years. Objections from the palliative care community have hitherto been largely based on Judeo-Christian and Humanistic perspectives. In this study the authors argue that the theoretical underpinnings of Buddhist practice also have the potential to add constructively to the debate, without reference to metaphysics. Aims The aim of this study was to examine traditional Buddhist texts as a means of discovering an alternative set of arguments relevant to palliative care and PAS in terminal illness. Methods As traditional Buddhist texts make no specific reference to palliative care or PAS, all passages which mention death, dying, illness, killing, kindness, intentionality and moral precepts contained within the five volumes of the Pali Sutta Pitika (the earliest recorded discourses of the Buddha) were selected for analysis. Using an inferential approach, several arguments relevant to palliative care and PAS were revealed. These were then tested for validity by checking for internal consistency within the texts and by analysis using modern applied ethics methods, namely Kantian, consequentialist, virtue ethics and four principles approaches. Results Several valid arguments in favour of palliative care and against PAS were discovered. Of note are the arguments from karma (that to care for the terminally ill potentially has beneficial effects on carers for the rest of their lives and that to assist in helping others to die has opposite, negative effects), transience (that the inevitability of death makes PAS ultimately unnecessary) and understanding (that for patients embracing life, despite inherent suffering, it can support the cultivation of wisdom and compassion, which benefit the individual and their community). Conclusions The analysis of traditional Buddhist texts provides novel, strong and relevant arguments in favour of palliative care in terminal illness, and against PAS.


e21008 Background: NUT midline carcinoma (NMC) is an aggressive squamous cell carcinoma molecularly defined by a chromosomal rearrangement of nuclear protein in testis (NUTM1) with bromodomain-containing protein 3 or 4 (BRD3/4). While NMCs are characterized by this rare canonical gene rearrangement little is known about the transcriptome and proteosome of this rare disease. As such, we set out to comprehensively characterize five NMC cases in which we attained targeted DNA sequencing, full-transcriptome RNA sequencing, and targeted proteomics. We further examine and integrate these results in order to better understand the relationship between gene expression and protein abundance within the context of NMC. Methods: All cases were analyzed for genomic and transcriptomic alterations against a custom panel via the Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth and full-transcriptome RNA sequencing) for germline and/or somatic mutations. The xT assay detects single nucleotide variants, specific insertion/deletions, amplifications and gene fusions, as well as tumor mutational burden (TMB) and microsatellite instability (MSI) status. Proteomic data were obtained utilizing digital spatial profiling through Nanostring immune, MAPK and PI3/AKT, and pan tumor nCounter GeoMix panels. Results: Clinical characteristics, histology, and genomic/proteomic alterations for 5 NMC cases are presented. Cases were defined by pathological assessment and the identification of the canonical NUTM1 fusion, further broken down by fusion partner with three patients having NUTM1-BRD4 fusions, one NUT-BRD3, and one NUT-ZMYND8. TMBs ranged for 0.8-.6 mutations/megabases (n=5). All patients were MSI stable (5/5). Of three patients with available PD-L1 IHC result, one had elevated PD-L1 tumor staining at 70%. Results will be presented from full-transcriptome RNA expression analysis indicating overexpression of BRAF, MYC, mTOR, and EGFR, among others. Targeted proteomics were performed to assess relative abundance at the protein level (results to be presented). Clinical follow up for the five patients revealed that two have survived beyond 7 months. A lung primary patient treated with surgical resection and post op radiation (XRT) is NED at 63 months. A sinus primary patient is NED at 16 months after a partial response (PR) to taxotere/5FU/Cisplatin followed by resection and XRT/cis platin. One patient had a brief PR from ifosphamide/etoposide/vorinostat. One patient's tumor grew through XRT/cisplatin. Conclusions: Multi-omic analysis has the potential to further elucidate the mechanisms of tumor growth in NMC and identify new targets for the treatment of this aggressive and poor prognosis disease.


The final result will be the same. This shows that the ray emerging after three reflections is parallel to the original ray. Finally, we consider the special occurrence of a ray entering the cube comer parallel to one of its faces. This case can be viewed as if the reflections take place on a billiard table, with a ball hitting successively two concurrent sides of the table; the answer is the same.


Introduction Measuring azathioprine or mercaptopurine (AZA) metabolite levels 6-TGN and 6-MMPN allows identification of patients who are: 1. Non compliant with their medication, 2. On a sub-optimal doe, 3. On a supra-therapeutic dose, 4. Are preferentially metabolising azathioprine to methylated metabolites (6-MMPN:6-TGN ratio > 11). Our own and others published data demonstrate that measuring metabolite levels in patients failing azathioprine therapy followed by appropriate changes in dosing and/or the addition of allopurinol (with 75% dose reduction in AZA) can result in clinical remission in the majority of patients 1. We report the outcome of the routine measurement of metabolite levels in patients treated with AZA who were in a clinical remission without side effects or abnormal liver function tests (LFTs). Methods All patients underwent TPMT testing, azathioprine and mercaptopurine were initiated at doses of 2mg/kg and 1mg/kg respectively in those with wild-type TPMT with a 50% reduction in dose in TPMT heterozygotes. We searched the prospective database maintained by our biochemistry department for all patients who underwent metabolite level testing from September 2011 to November 2012, hospital case notes for these patients were reviewed. The indications, results of testing, changes in clinical management and patient outcomes were recorded. Results 108 patients underwent metabolite testing, median length of follow-up since testing was 287.6 days (range 21–441), all were stable on AZA for > 4 weeks with normal LFTs and in a clinical remission. 38 (35.2%) had UC, 66 (61.1%) CD, 52 (48.1%) were male. 17 (15.7%) patients had a sub-theraputic 6-TGN, 10 (9.3%) supra-theraputic 6-TGN level (> 800) all of whom had dose optimisation. 6 (5.6%) patients were hypermethylators these were switched to allopurinol co-therapy with an appropriate reduction in AZA dose. Conclusion In the present study the routine measurement of AZA metabolites resulted in a change in clinical management in 30.6% of patients. Whilst unproven in prospective longitudinal studies logic suggests that the routine measurement of AZA metabolites in all patients commenced on thiopurines followed by appropriate dose optimisation (with or without allopurinol co-prescription) should reduce or prevent the development of drug side effects, abnormal LFTs and bone marrow suppression and reduce the risk of disease relapse. We recommend that AZA metabolite testing is performed in all patients 4–6 weeks after commencing AZA. Disclosure of Interest None Declared.


Building projects often experience cost and time overruns. This problem is common across the world but it appears to be more pronounced in many developing countries such as Kenya. These overruns, depending on their magnitude can develop into major risks which will threaten the success of these projects. This research surveyed a total of one hundred and twenty (120) building projects and their cost and time overruns were determined. These overruns were used to develop fictional relationships with the probability of both the cost overruns and used to develop prediction equations. The models developed may be used to predict the risk (magnitude) for cost and time overruns for various types of building projects. These predictions should form a basis for allocating risks to various parties involved in building projects.


BACKGROUND AND PURPOSE
Renal mass protocol CT (RMP-CT) using multiphase abdomen and pelvis CT imaging is the mainstay for diagnosis, characterization, and follow-up for renal masses; however, it is associated with ionizing radiation to the patient. We sought to quantify the effective dose associated with RMP-CT and to determine how patient factors affect radiation exposure.

MATERIAL AND METHODS
We retrospectively reviewed the records of 247 patients undergoing management of a small renal mass (cT1a) between 2005 and 2011 at our institution. Body mass index (BMI) was categorized as normal weight, overweight, obese, and morbidly obese (≤25, 25.1-30, 30.1-35 and >35, respectively). Effective dose of RMP-CT was calculated through the dose-length-product multiplied by a factor coefficient (0.015). Effective doses in milliSieverts (mSv) were correlated to patient characteristics.

RESULTS
Patients' median age was 61 years, and median BMI was 28.7 kg/m(2); 72% were Caucasian and 56% were male. Median effective dose was 26.1 mSv (interquartile range 20.6-35.3). When stratified by BMI, the median effective doses were 18.9, 25.2, 27.7, and 36.2mSv for normal weight, overweight, obese, and morbidly obese patients, respectively. On multivariable analyses, BMI and male sex were significantly associated with increased radiation dose.

CONCLUSIONS
In this series, the median effective dose for RMP-CT was 26.1 mSv. Obesity was independently associated with markedly increased radiation exposure, with morbidly obese patients being exposed to almost twice the amount of radiation compared with normal weight persons. These findings should be considered when devising management strategies in patients with a renal mass and strategies should be developed to reduce medical ionizing radiation exposure.


The dominant paradigm for the evolution of mutator alleles in bacterial populations is that they spread by indirect selection for linked beneficial mutations when bacteria are poorly adapted. In this paper, we challenge the ubiquity of this paradigm by demonstrating that a clinically important stressor, hydrogen peroxide, generates direct selection for an elevated mutation rate in the pathogenic bacterium Pseudomonas aeruginosa as a consequence of a trade-off between the fidelity of DNA repair and hydrogen peroxide resistance. We demonstrate that the biochemical mechanism underlying this trade-off in the case of mutS is the elevated secretion of catalase by the mutator strain. Our results provide, to our knowledge, the first experimental evidence that direct selection can favour mutator alleles in bacterial populations, and pave the way for future studies to understand how mutation and DNA repair are linked to stress responses and how this affects the evolution of bacterial mutation rates.


This paper presents the design of a reconfigurable successive approximation analog to digital converter (ADC) for both ultra wideband and Bluetooth applications. The behavioral level design is presented along with the circuit implementation. The ADC architecture employs a split capacitor array DAC which reduces the power consumption. The ADC is implemented in a 0.18mum CMOS process and circuit level simulation results show that the ADC can achieve 28.9 dB SINAD at 66 MSPS in the UWB mode, and 53.9 dB SINAD at 1 MSPS in the Bluetooth mode.


Individuals with a highly defensive personality style tend to present themselves in an overly favorable light and deny personal inadequacies. Following traumatic brain injury (TBI), denial may be an adaptive strategy to protect individuals from the overwhelming reality of their situation. However, persisting denial can interfere with the adjustment process and hinder the development of more adaptive coping strategies. A case study is presented of JK, a 45-year-old woman with a highly defensive personality style, who sustained a TBI. JK developed social anxiety and depression and was referred for psychological support following a progressive deterioration in her overall functioning. The treatment program was based on an individual-psychotherapy approach, with generalization of skills in a group-therapy setting. A comparison of pre- and posttreatment functioning indicated a significant reduction in her level of social anxiety, depression, defensiveness, and functional impairment. Independent neuropsychological assessments, conducted for medico-legal purposes, prior to and following the intervention, indicated a significant improvement in JK's cognitive performance between periods of testing. The implications of this study are discussed in terms of the impact of defensive denial upon postinjury adjustment and therapeutic approaches.


Geoscience visualizations are commonplace; they appear in television news pro- grams, classroom lectures, conference presentations, and internet hypermedia. But to what degree do individuals who view such visualizations actually learn from them, and if so, why? As visualizations become more commonplace in school, laboratory, and entertainment settings, there has been a concurrent interest in considering the effectiveness of such presentations. How can we build effective collaborations that address pedagogical questions in the earth sciences while also informing theories about the cognitive processes that underlie visualization experiences? In this chapter, we contend that only through directed, collaborative projects between earth scientists and cognitive scientists will significant advances in visualization research take place. We describe two specific models of such collaboration, the advisory model and the reciprocal model, and argue that a reciprocal model presents a more effective frame- work for addressing important questions about the nature of the visualization experi- ences. Such a model will inform both the design of effective visualizations for teaching complex geoscience topics, as well as provide insight into the processes that underlie learning from visualizations.


Summary: The keystone represents the union of six distinct anatomical structures between the bony vault and the cartilaginous midvault. In reshaping the nasal dorsum, the individual components of the nose respond variably as the fusion points of the keystone are released. In restoring the nasal dorsum, meticulous effort is made to equalize the width between the bony vault and the cartilaginous midvault. Techniques used for width equalization will yield gratifying long-term results and avoid common pitfalls such as the inverted-V deformity.


Designing cost-effective and scalable on-chip multi-processors demand careful attention be paid to software. In particular, if not optimized, the energy consumption due to interprocessor communication can be overwhelming. In this paper, we focus on array-intensive applications and study the energy impact of inter-processor communication optimizations on a private memory based on-chip multi-processor. Our results emphasize the importance of considering both computation energy and communication energy when applying optimizations that reduce inter-processor communication.


On January 7, 1997, Dallas-Fort Worth International Airport experienced its first large bird strike event, involving the collision of over 350 European starlings with an American Airlines MD-80. This prompted a serious assessment of existing wildlife control procedures, and eventually resulted in the formation of the DFW Wildlife Control Program. The number of reported strikes has dropped from 157 in 1996 to 52 in 1998. The success of DFW's program is the result of long, hard hours and extensive trial and error. However, wildlife management personnel at other airfields do not have to go through all the growing pains and exertions that DFW encountered. This paper describes the evolution of the DFW Wildlife Control Program, and provides wildlife control personnel and administrators with information that would reduce the hassle and heartache associated with starting a wildlife control program. Furthermore, this paper describes the useful and often necessary roles of consultants in establishing and monitoring airfield wildlife control programs.


MPromDb (Mammalian Promoter Database) is a curated database that strives to annotate gene promoters identified from ChIP-seq results with the goal of providing an integrated resource for mammalian transcriptional regulation and epigenetics. We analyzed 507 million uniquely aligned RNAP-II ChIP-seq reads from 26 different data sets that include six human cell-types and 10 distinct mouse cell/tissues. The updated MPromDb version consists of computationally predicted (novel) and known active RNAP-II promoters (42 893 human and 48 366 mouse promoters) from various data sets freely available at NCBI GEO database. We found that 36% and 40% of protein-coding genes have alternative promoters in human and mouse genomes and ∼40% of promoters are tissue/cell specific. The identified RNAP-II promoters were annotated using various known and novel gene models. Additionally, for novel promoters we looked into other evidences—GenBank mRNAs, spliced ESTs, CAGE promoter tags and mRNA-seq reads. Users can search the database based on gene id/symbol, or by specific tissue/cell type and filter results based on any combination of tissue/cell specificity, Known/Novel, CpG/NonCpG, and protein-coding/non-coding gene promoters. We have also integrated GBrowse genome browser with MPromDb for visualization of ChIP-seq profiles and to display the annotations. The current release of MPromDb can be accessed at http://bioinformatics.wistar.upenn.edu/MPromDb/.


Background: As companies are operating in more globally and complex environments, the need for risk control is accelerating. In an ever-changing environment, companies cannot merely focus on traditional risks, which include financial and insurable risks. To maintain competitiveness, companies need to extend their risk management to include all risks, traditional as well as operational and strategic risks. Purpose: The purpose is to describe and position risk management for Telecom operators, in comparison with the risk management literature, with regards to structure, processes, learning process, visions and benefits. In addition, our aim is to link risk management perspectives with the different strategies for knowledge management. Method: The approach taken is a hermeneutic case study, in which a total of 13 in-depth interviews with three different Telecom operators have been carried out. Results: The main findings are that the Telecom operators have developed their risk management to the business risk management perspective. There are some indications however that the companies are focusing on widening their risk management to the Enterprise-Wide perspective. The degree of the environments complexity, in which companies are operating, is determining the need for different risk management perspectives. To maintain their competitiveness in a highly complex environment a wider risk management perspective is needed. This includes operational and strategic risks, which are non-quantifiable. Therefore the personalization strategy is to recommend for achieving an effective risk management. A less complex environment, on the other hand, can mainly focus on the traditional risks. These risks are quantifiable, and therefore the codification strategy is to prefer.


Shaking by moderate to large earthquakes in the Mediterranean Sea has proved in the past to potentially trig- ger catastrophic sediment collapse and flow. On 21 May 2003, a magnitude 6.8 earthquake located near Boumerd` es (central Algerian coast) triggered large turbidity currents re- sponsible for 29 submarine cable breaks at the foot of the continental slope over 150 km from west to east. Seafloor bathymetry and backscatter imagery show the potential im- prints of the 2003 event and of previous events. Large slope scarps resulting from active deformation may locally en- hance sediment instabilities, although faults are not directly visible at the seafloor. Erosion is evident at the foot of the margin and along the paths of the numerous canyons and val- leys. Cable breaks are located at the outlets of submarine val- leys and in areas of turbiditic levee overspilling and demon- strate the multi-source and multi-path character of the 2003 turbiditic event. Rough estimates of turbidity flow velocity are not straightforward because of the multiple breaks along the same cable, but seem compatible with those measured in other submarine cable break studies elsewhere. While the signature of the turbidity currents is mostly ero- sional on the continental slope, turbidite beds alternating with hemipelagites accumulate in the distal reaches of sed- iment dispersal systems. In perspective, more chronological work on distal turbidite successions offshore Algeria offers promising perspectives for paleoseismology reconstructions based on turbidite dating, if synchronous turbidites along independent sedimentary dispersal systems are found to sup- port triggering by major earthquakes. Preliminary results on sediment core PSM-KS23 off Boumerd` es typically show a 800-yr interval between turbidites during the Holocene, in accordance with the estimated mean seismic cycle on land, even if at this stage it is not yet possible to prove the earth- quake origin of all the turbidites.


1. In the development of the post-2015 development agenda, the water-education nexus offers opportunities for dealing with a variety of different sustainable development challenges including: inequity in education, disaster recovery, and local mobilization. 2. In order to respond to water-related sustainability challenges, people worldwide need to acquire "water literacy." The term is used here to refer to appropriate knowledge about various aspects of water use and management in order to ensure safer water consumption and to contribute to Disaster Risk Reduction (DRR). We believe that water literacy can be acquired by obtaining basic literacy competencies and a certain level of education. 3. In order to create opportunities for people to gain the knowledge and skills they need so that they can respond effectively to water-related sustainability challenges, it is essential that government representatives and other stakeholders acquire an accurate understanding of water-related issues and that systems be established for implementing concrete measures.


For over a century the UK has experienced relative long-term economic decline, as evidenced by its disproportionate loss of world trade and slow growth rate when compared to Germany and other OECD economies. This thesis examines whether sterling overvaluation has been the cause of this decline and the UK's current economic dilemma.
Thirlwall, (2011) wrote:
'foreign exchange is a major constraint on the growth performance of many poor countries and that with improved export performance and a lower income elasticity of demand for imports, they would grow much faster.'
Would a more competitive pound relieve the UK of a balance of payments constraint or would it cause inflation, depress living standards and leave structural problems unaddressed?
The thesis analyses the pro and anti-devaluation arguments. The pro-devaluation demand-side argument rests on the supposition that UK economic policy has long favoured finance over industry causing sterling to be overvalued, arguably since its original overvaluation in 17111. This has drawn investment and human capital away from manufacturing which in turn exacerbates supply-side deficiencies.
The UK's long-term trade deficit on goods has been financed through a combination of a surplus on invisibles and a reliance on income from overseas assets. In this decade net income streams have turned negative leaving the UK dependent on foreign direct investment and further sell-offs of UK assets both at home and abroad.
The thesis argues that this is unsatisfactory because:
1. In the short and medium-term it creates unemployment and a hugely unequal and polarised society.
2. In the long run it is unsustainable, as when there are insufficient assets left to sell, the inevitable unplanned exchange rate crash will occur.
The thesis finds that overvaluation causes a lack of investment in those parts of the economy where productivity increases are readily achieved and a lack demand which induces either deflation or the unsustainable substitution of private debt. When private debt creation slows, this induces a rise in government debt. Without a competitive currency, the UK faces a balance of payments constraint or a burgeoning and unsustainable debt burden. This exacerbates inequality and risks the breakdown of consensual politics.

1 In 1711 Newton, as Master of the Mint, reluctantly valued sterling at £3 17sh 6d to the ounce of gold; see page 93 for concluding summary on this theme.


Problem. A malfunction of the service braking system of a wheeled vehicle (CTS) significantly affects road safety, especially when operating multi-axle vehicles with large masses. One of the ways to increase the level of road safety of multi-axle vehicles, when braking them using a spare (emergency) braking system, is the introduction of automated adaptive braking systems into the design of the brake drive of vehicles. The definition of the limits of the use of the adaptive braking system on vehicles with many axles is almost not disclosed in the scientific and technical literature, therefore, the issue of using such a system on vehicles with a large number of axles requires additional research. Purpose. The purpose of this work is to develop a simulation model for adaptive control of the braking process of a multi-axle vehicle using a spare (emergency) braking system, taking into account the simulation of the dynamics of the drive and the variability of the adhesion properties between the tire of the vehicle wheel and the road surface. Methodology. To achieve this goal, it is necessary to develop a simulation model of the brake drive in an adaptive mode, implement a model of the interaction of the tire with the road surface, and implement a model of the braking dynamics of a multi-axle vehicle in the event of a malfunction of its service brake system. Originality. The proposed key criterion (Kr) for changing the throttle section in electro-pneumatic pressure modulators, which provide adaptive air inlet or outlet from the corresponding brake chambers of the drive, during simulation, made it possible to simulate the operation of the drive circuits in the adaptive mode. It has been established that, depending on the potential for the realization of the adhesion between the tires of automobile wheels and the road surface, the pressure in the electro-pneumatic brake drive with its adaptive regulation can be increased by no more than 0.04 MPa.


A collection of primitive titanosauriform sauropods from the Jones Ranch locality, Early Cretaceous Twin Mountains Formation (~112 Ma), central Texas, represents one of the richest accumulations of sauropod bones in North America. Autapomorphic characters of the taxon include cranial and mid-caudal neural arches with distinct intraprezygapophyseal laminae (tprl), accessory vertebral laminae on cranial dorsal neural arches, and dorsal neural spines that lack a postspinal lamina. Non-vertebral skeletal elements referred to the genus Pleurocoelus from the Arundel Formation of Maryland and Virginia possess some diagnostic morphological characteristics and can be compared with the Jones Ranch sauropod. The latter differs from Pleurocoelus in the shape of the caudoventral margin of the maxilla, the shape of the distal scapular blade, and the shape of the proximal condyle of the tibia. The Jones Ranch sauropod is also morphologically distinct from all other sauropods described and named from the Early Cretaceous of North America. Cladistic analysis places this sauropod within Titanosauriformes. The Texas sauropod does not possess synapomorphies of Somphospondyli, and derived characters that have been used to define the Titanosauria are also absent, affirming its placement as a basal titanosauriform. The new taxon from Texas is known from more material than any other North American Early Cretaceous sauropod. Description of the taxon increases the diversity of sauropods in North America during the Early Cretaceous and provides more complete, associated material that can be compared to new discoveries from this time period. Department of Geological Sciences, Southern Methodist University, Dallas, Texas, U.S.A. Current address: Department of Geology and Geophysics, University of Minnesota, Minneapolis, Minnesota, U.S.A. email@example.com


There is a common belief that mammalian cell gene mutation assays are prone to false
positives, thus questioning the relevance of these tests in regulatory screening paradigms and
the mechanisms responsible for these uninterruptable results. False positives can lead to
unnecessary animal testing and delays in the development of efficacious new medicines. The
initial aim of this thesis was to put into perspective the rate of positives and firstly to consider the
extent off target aneugenicity (chromosome loss or gain) may contribute to this rate. Secondly
the contribution of topoisomerase II poisoning and its relationship to genotoxicity was
considered. Topoisomerase II maintains DNA topology by inducing transient breaks in one
strand so a second strand can pass. Chemicals that interact with the enzyme (topoisomerase II
poisons; e.g. the antibiotic gemifloxacin and the chemotherapeutin etoposide), yield
topoisomerase II bound DNA cleavage complexes, making breaks permanent, leading to
mutation or cell death. Structurally, topoisomerase II poisons are diverse, so their genotoxicity
is difficult to predict.
To estimate the incidence of positives seen in pharmaceutical research, a retrospective review
of data from 10 years of mouse lymphoma assays (MLA) conducted at AstraZeneca was
undertaken. This showed that the rate of unexplainable positives was only 5%, vindicating the
use of the test in screening paradigms. Consideration was then made of what mechanisms
might contribute to this 5%. Aneugenicity was considered but it was shown that the MLA was a
poor screen, failing to identify 7 known anuegens.
To gain a better understanding of the relationship between topoisomerase II and genotoxicity,
assays to assess enzyme poisoning were examined, including the ability of the cell free
decatenation assay to predict the results of the in vitro micronucleus test. However, even when
combined with an estimate of cellular uptake the predictivity was low.
Assays to investigate topoisomerase II poison / DNA cleavage complexes in vivo were then
investigated. The TARDIS and ICE assays both use antibodies to target topoisomerase II
bound in the complex. TARDIS was found to be insensitive, failing to identify cleavage complex
formation with gemifloxacin. Using the ICE assay, cleavage complex formation was seen for
etoposide (0.1 μmol/L; FITC intensity 3.53 ± 0.79) and gemifloxacin (100 μmol/L; FITC intensity
3.37 ± 0.86), but not at equivalent concentrations to those inducing micronuclei (MN) (0.03
μmol/L etoposide; MN/1000 6 ± 2.6 and 10 μmol/L gemifloxacin; MN/1000 5 ± 3.4), thus
questioning assay sensitivity, or suggesting a role for other mechanisms of genotoxicity e.g.
reactive oxygen species (ROS).
The hOGG Comet assay showed that neither etoposide nor gemifloxacin induced ROS related
genotoxicity.
Improvements to the sensitivity of the cleavage complex assays were made by preparation of
mouse specific antibodies, but TARDIS was still unable to identify gemifloxacin. This work also
suggested that when developing antibodies for DNA bound topoisomerase II, the n-terminus of
the enzyme should be targeted.
Over the last 4 years, emerging data linked the topoisomerase IIβ isoform to genotoxicity. As
research within this thesis had investigated the activity of topoisomerase IIα, this may have
explained the difficulty encountered equating topoisomerase II poisoning to genotoxicity.
Following siRNA knockdown of topoisomerase IIα, the genotoxicity of etoposide and
gemifloxacin was investigated. It was shown that for 0.3 μmol/L etoposide, topoisomerase IIα
knockdown of 42% (± 2%) was associated with a reduction in micronuclei of 49% (± 9.7%). For
30 μmol/L gemifloxacin, topoisomerase IIα knockdown of 37% (± 9.5%) was associated with a
reduction in micronuclei of 48% (± 0.2%). This was the first time such direct relationships had
been demonstrated between the alpha isoform and genotoxicity.
In conclusion, the predictivity of the MLA was confirmed but it was clear the assay is not a
suitable screen for aneugenicity. The relative sensitivity of assays to measure topoisomerase II
poisoning was shown and linked to genotoxicity. Whilst it was not possible to demonstrate
cleavage complex formation at concentrations below which genotoxicity was seen, this was
likely due to the insensitivity of the assays used rather than topoisomerase II poisons having
other genotoxic mechanisms. For the first time the link between topoisomerase IIα and
genotoxicity was confirmed and use of knockdown cells holds real promise as a tool for
investigating off target topoisomerase II poisoning.