The NASA's Earth Polychromatic Imaging Camera (EPIC) on board the Deep Space Climate Observatory (DSCOVR) satellite has been making multiple observations of the entire sunlit Earth in a given day from the Sun-Earth Largangian L1 point since the summer of 2015. EPIC contains 10 narrow channels in the 317–780 nm solar spectral range. The data acquired with EPIC have already been used in a variety of scientific investigations, including the study of the global ozone levels, aerosol index and aerosol optical depth, UV reflectivity of clouds over land and ocean, cloud height over land and ocean, and vegetation indices. In this article, we report that EPIC data, particularly for the data measured with narrow channels centered near 443, 551, and 680 nm, can also have important applications in remote sensing of ocean color in different geographical regions. We have modified a version of a multi-channel atmospheric correction algorithm for Moderate Resolution Imaging SpectroRadiometer (MODIS) ocean color applications and adapted the algorithm for processing EPIC data. We present three case studies on water leaving reflectance retrievals from EPIC data acquired over a large turbid river, inland lakes, and oceans. We conclude that a future ocean color instrument on board a satellite at the L1 point, which provides continuous view of the full sunlit disk of the Earth, will complement and extend ocean color observations with the low Earth observing polar orbital and geostationary satellite instruments in both the spatial and time domains.


We are analysing the wheat pathogen Stagonospora nodorum in order to determine the molecular basis of pathogenicity. The genome sequence of the wheat pathogen Stagonospora nodorum is the first Dothideomycete to be released. This taxon includes a large number of important plant pathogens. The sequence has facilitated experiments that have defined roles for the Ca2+/calmodulin, MAP kinase and cAMP-dependant signalling pathways and for the metabolites mannitol, arabitol, xylitol, malate, trehalose and aminolevulinate. Analysis of gene expression throughout infection points to three phases of nutrition; a lipolytic phase utilising internal stores; a glycolytic phase using external low molecular weight assimilates and hydrolytic phase using external polymerised substrates. The Dothideomycete group includes most or all pathogens that produce host-specific toxins. ToxA is produced by Pyrenophora tritici-repentis, the causal agent of tan spot in wheat and is responsible for virulence of the fungus on wheat genotypes carrying the dominant susceptibility gene Tsn1. A S. nodorum predicted gene, SnToxA is nearly identical to PtrToxA. Disruption of SnToxA significantly reduced disease on wheat lines carrying Tsn1. Sequencing of ToxA genes from a world wide collection of isolates of P. tritici-repentis and S. nodorum showed that all the P. tritici-repentis sequences were identical but that the S. nodorum sequences were highly variable. This pattern is strong evidence of horizontal gene transfer from S. nodorum to P. tritici-repentis. Furthermore, comparison of the sequences showed an excess of non-synonymous codon changes over synonymous, suggesting diversifying selection. This is expected of a protein that interacts directly and significantly with the product of Tsn1. P. tritici-repentis is a recently emerged disease and we suggest this emergence is linked to the acquisition of ToxA, prior to 1941, that enabled the rapid spread around the world. SnToxA is one of several toxins produced by S. nodorum. These studies raises several important and new problems. These include the effect of toxin possession and expression on the fecundity and survival of fungal strains carrying the toxins, the history of the possession and expression of toxin receptor genes in the host wheat and the mechanisms of sequence diversification in toxin genes. Progress in these areas will be described.


A vigorous attack on moral responsibility in all its forms argues that the abolition of moral responsibility will be liberating and beneficial. In Against Moral Responsibility, Bruce Waller launches a spirited attack on a system that is profoundly entrenched in our society and its institutions, deeply rooted in our emotions, and vigorously defended by philosophers from ancient times to the present. Waller argues that, despite the creative defenses of it by contemporary thinkers, moral responsibility cannot survive in our naturalistic-scientific system. The scientific understanding of human behavior and the causes that shape human character, he contends, leaves no room for moral responsibility. Waller argues that moral responsibility in all its forms-including criminal justice, distributive justice, and all claims of just deserts-is fundamentally unfair and harmful and that its abolition will be liberating and beneficial. What we really want-natural human free will, moral judgments, meaningful human relationships, creative abilities-would survive and flourish without moral responsibility. In the course of his argument, Waller examines the origins of the basic belief in moral responsibility, proposes a naturalistic understanding of free will, offers a detailed argument against moral responsibility and critiques arguments in favor of it, gives a general account of what a world without moral responsibility would look like, and examines the social and psychological aspects of abolishing moral responsibility. Waller not only mounts a vigorous, and philosophically rigorous, attack on the moral responsibility system, but also celebrates the benefits that would result from its total abolition.


The Zaneis and Kingfisher series are both developed from Permian "Red Bed" deposits and occur primarily in the Reddish Prairie Provinces of Oklahoma, Kansas, and Texas. Four profiles of the Zaneis series and two profiles of the Kingfisher series were sampled in detail. Chemical and physical studies were made on each subhorizon. Clay mineralogical studies were made for each major horizon. The clay was separated into two fractions: 2 to 0.2µ and < 0.2µ. Ethylene glycol retention, nonexchangeable K, cation-exchange capacity, differential thermal, and X-ray diffraction analyses were made. Results show the clay fractions of all six profiles contain a high percentage of particles < 0.2µ in diameter. Montmorillonitic-type minerals dominate the fine clays of all six profiles while illite, vermiculite, and kaolinite are dominant in the coarse clays. Very little evidence of weathering of clay minerals was found. Apparently the clay minerals present in the solum are, for the most part, inherited directly from the clay minerals present in the parent materials. The parent materials of the Kingfisher soils were found to differ in character from those of the Zaneis. The soil materials of the Kingfisher soil appear to have been deposited in brackish water; whereas, those of the Zaneis were deposited in more fresh water.


Two-photon laser-induced fluorescence spectrum (TP-LIF) of NO is obtained with a Nd:YAG pumped optical parametric generator and amplifier as radiation source. Spectral intensity distribution shows that the electronic transition moment for NO (A^(2)? ? X^(2)?) transition varies significantly with inter-nuclear distance. The variation relationship of the electronic transition moment versus inter-nuclear distance is deduced with polyminal fit procedure. The spontaneous radiative coefficients for NO (A^(2)? ? X^(2)?) transition from ?' = 0, 1 are obtained by combing this transition moment variation with the measurements of spontaneous radiative lifetime.


This thesis investigates the changing cinematic representations of a particular figure in horror culture: the Zombie. Current critical perspectives on the figure of the Zombie have yet to establish literary and cultural antecedents to the cinematic portrayal of the Zombie, preferring to position it as a mere product of American horror films of the 1930s. This study critiques this standpoint, arguing that global uses of the Zombie in differing media indicate a symbolic figure attuned to changing cultural contexts. The thesis therefore combines cultural and historical analysis with close textual readings of visual and written sources, paying close attention to the changing contexts of global film production and distribution.
In order to present the cinematic Zombie as a product of historical, geographical and cultural shifts in horror film production, the thesis begins by critiquing existing accounts of Zombie film, drawing attention to the notion of generic canons of film as determined by both popular and academic film critics and draws attention to the fractured nature of genre as a method of positioning and critiquing film texts. In this, an interdisciplinary approach, drawing on the methods of cultural-historical and psycho-analytical critiques of horror film, is appraised and then applied to the texts under discussion. The first chapter positions a working thematic and visual deconstruction of the Zombie as an embodiment of the abject, positioning it as a result of changing cultural discussions in fiction on the nature of death and burial. This establishes a thematic framework to apply throughout the following chapters, noting alterations to representations. The second chapter offers a historicised account of appearances of the fictional Zombie before American cinematic productions of the 1930s, critiquing claims that this is the only original production context for the Zombie. The third chapter charts the changing production contexts of American Zombie film until the mid 1960s, to introduce the critiques of authorial importance placed upon the works of George A. Romero, which are discussed in Chapter 4. This critique in turn questions established notions of generic canon and international influence, which are discussed in Chapters 5 and 6. These chapters question the idea of American filmic product dominance in national contexts, charting the discussions of the Zombie body found in differing national cinemas. It is shown that dialogues of representation can be both nationally specific and meant for global audiences, brought about by the changing production and exhibition markets of the 1970s onwards. This in turn challenges the idea that the American model is the dominant representation in the contemporary Zombie film, discussed in Chapter 7.
The thesis therefore charts three separate areas for discussion, that of historical, cultural and production contexts that can be held accountable for changing cinematic representations. Particular attention is placed on the thematic and visual use of the Zombie within differing media and firmly position cinematic representations as indicative of wider changes in popular media and their intended audiences. The thesis therefore offers a detailed historical and cultural taxonomy of Zombie film, furthering previous studies, but also presents a more detailed exploration of cultural contexts than previous critics have attempted.


The presence of moral evil (sin) in the world is relatively easy for the Christian creationist to explain, and free choice is key to that explanation. To Christian evolutionist and professor of biology Daniel Brannan, the idea of a very good Creation and an Adam and Eve who were deceived and sinned is not only incoherent but also makes God the cause of sin. Brannan proposed that Christians accept an Irenean sense of original sin, which entails that Adam was essentially an undeveloped child. Adam was deceived by Satan because he was incapable of distinguishing right from wrong, and Adam had no free choice. How could Adam and Eve have chosen between good and evil, when only after eating of the tree did they achieve that ability? How could they even have been responsible for their choosing, when their eyes were open only after their choice and eating? This paper will show that Brannan's arguments are based on faulty premises regarding Adam's constitutional nature, the nature of Adam and Eve's perfection and Adam's power of free choice. Adam was not deceived, and God is not the cause of sin.


Channeling Ebola virus entry into the cell The current outbreak of Ebola virus in West Africa highlights the need for antiviral therapies. One strategy would be to block the Ebola virus's ability to enter host cells. Cells engulf Ebola virus particles, which then traffic into the cell in structures called endosomes. Sakurai et al. now report that the Ebola virus requires calcium channels called two-pore channels (TPCs) in endosomal membranes for successful entry (see the Perspective by Falzarano and Feldmann). The Ebola virus could not enter cells lacking TPCs or cells treated with a TPC inhibitor. Blocking TPCs therapeutically allowed 50% of mice to survive an ordinarily lethal Ebola virus infection. Science, this issue p. 995; see also p. 947 Ebola virus requires endosomal two-pore calcium channels to enter host cells. [Also see Perspective by Falzarano and Feldmann] Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy.


Alternative medicine has renewed its growing public interest in recent times due to inequality of patients and healthcare professionals' ratios with increased workload for the latter, various side effects of modern medicine, lack of complete remission from chronic diseases, high cost of new drugs, and emerging new diseases. Hence, people have become more dependent on treatment systems replying on alternative medicine or herbal medicine from traditional medicinal practitioners. Alternative medicine has grown substantially over time and encompasses several millennia of therapeutic systems. The significant areas of alternative medicine include mind–body therapies, body manipulation, and the therapies based on biological systems. Natural products based biological treatment is the most popular of them as nature has endowed us with abundance of effective pharmacologically active phytochemicals. These phytochemicals possess numerous specific clinical health benefits including antioxidant, antidiabetic, anti-inflammatory, anticancer, anti-infectious and analgesic effects. In addition, alternative medicine is easily accessible, affordable, most often noninvasive, and provides favorable benefits during terminal periods of some diseases. However, due to the lack of well-designed clinical trials, the safety and effectiveness of many alternative medicines/therapies remains elusive. This chapter will critically discuss major areas, uses, safety and regulation, current challenges & future perspectives of alternative medicine.


Firms' inability to commit to future funding choices has profound consequences for capital structure dynamics. With debt in place, shareholders pervasively resist leverage reductions no matter how much such reductions may enhance firm value. Shareholders would instead choose to increase leverage even if the new debt is junior and would reduce firm value. These asymmetric forces in leverage adjustments, which we call the leverage ratchet effect, cause equilibrium leverage outcomes to be history†dependent. If forced to reduce leverage, shareholders are biased toward selling assets relative to potentially more efficient alternatives such as pure recapitalizations.


Lean Management has been successfully applied by companies around the world, mainly in production/manufacturing functions. Recently, the interest to investigate a wider application of Lean Management especially in service functions increased. However, it is not clear how Lean Management can be applied to IT organizations. Therefore, this study aims to provide an overview on common characteristics and future research directions. A literature review on existing scholarly research from January 2004 to June 2014 is conducted. Using a database-driven search approach, a total of 1,206 research contributions are found of which 49 were identified as relevant. Results indicate a low theory grounding of mostly formulative and interpretative research items. This implies that research on Lean Management of IT organizations is still at its nascent state. Content-wise, five research themes emerge. The majority of research investigates IT organizations in a role to support Lean Management in production/manufacturing functions (determining "what to work on"), therefore more research on how Lean Management can be applied to IT organizations themselves (determining "how to work") could be beneficial. Future research could also try to build on Change Management theories, as the implementation of Lean Management is of transformational character.


The deformed, low-grade, metasedimentary-volcanic schist belts of NW Nigeria, and the voluminous granitoid plutons which invaded them, are expressions of late Proterozoic-early Phanerozoic activity in the terrain separating the W African and Congo cratons. Recent interpretations of Nigerian geotectonic evolution have invoked two generations of schist belt, one a product of Kibaran (c. 1100 Ma) ensialic processes, the other due to Pan-African (700–450 Ma) marginal basin development. The detailed histories of the Anka Belt (Pan-African), Maru Belt (Kibaran) and Birnin Gwari Belt (unknown age), and the plutons emplaced in them, are documented here on the basis of new field, chemical and isotopic data.* Each belt represents a dominantly quiet-water sedimentary environment but volumetrically minor lithologies reveal important differences between the belts. The volcanic rocks and early minor intrusions have strong affinities with those of destructive plate margins. The schist belts were deformed congruently and simply before c. 750 Ma, following the development of flat-lying, possibly thrust-related structures in the Maru and Birnin Gwari Belts. Subsequent plutonism, beginning c. 750 Ma ago, has the calcalkaline, I-type characteristics of subduction zones but younger plutons have mildly peralkaline compositions due to thickening crust.


Training (whether traditional, e-learning, or blended learning) is intimately connected with and dependent on the human cognitive system. Learning means that the cognitive system acquires information and stores it for further use. If these processes do not occur properly, then the learners will not initially acquire the information, and even if they do, then they will not be able to recall it later, or/and the information will not be utilised and behaviour will not be modified. Regardless whether the objective is learning new information (e.g., compliance regulations, product specifications, etc.), acquiring new skills (e.g., operating a new apparatus, customer service, time management, etc.), or knowledge sharing and transfer within or across organisations — the processes of acquiring, storing and applying the information are critical. The question is how to achieve these cornerstones of learning and whether technology can enhance them. The answer is clear: The learning must fit human cognition. There is a lot of scientific knowledge and research on human cognition and learning. The difficult and tricky challenge is how to translate this theoretical and academic research into practical ways to utilise technology so as to enhance learning. By bridging basic research about learning and the brain into ways of using learning technologies, one is able to create sophisticated learning programs. These take into account and build on the architecture of cognition, and as a consequence produce effective and efficient technology enhanced learning.


Many efforts have been made lately to combat occupational noise exposure, and the situation in many industries concerning noise preventive measures seems promising. Conversely, with regard to recreational activities the situation seems less promising. There are reasons to raise concerns about noisy activities such as personal cassette players (PCPs), pop/rock concerts, car stereos, motor sport, shooting activities, etc. For most of the musically oriented activities the situation is probably generally satisfactory; even if the sound levels frequently are very high, the exposure time and number of exposures/year is limited. For impulsive noisy activities the situation is more serious. As is well known, the impulsive noise in connection with the use of weapons, fire‐crackers, and toy‐cap guns without hearing protection may lead to a permanent noise induced hearing loss under accidental conditions. The general attitude concerning recreational noisy activities should obviously be to strive for lower sound leve...


2. Nereidae 1). Nereis (Platynereis) striata (Schm.). (Mastigonereis striata Schm.). Of this species several specimens were collected in Table bay, where they were found for the first time by Schmarda 2) and afterwards met with by Willey 3). Unfortunately the description of the species is rather short and incomplete and the synonimy somewhat dubious; therefore I think it not superfluous to give a detailed account of them, especially while an epitocous male was among them. The specimens are rather small, measuring about 30 mm. in length, whereas the number of segments amounts to 70. The specimens of Schmarda and of Willey were somewhat larger, measuring 50 mm. in length, with about 80 segments. Nereis striata is characterized by a conspicuous coloration, consisting of a narrow, transverse, black band (dark violet in the living worm), which laterally becomes broader and acquires the shape of a brace, over the dorsal side of each segment; moreover there occurs a double black patch at the base of the dorsal cirri and an other one near the ventral cirri, whereas an interrupted black line runs in the median ventral line. Armature of the proboscis: maxillary region, I absent; II a narrow, semilunar patch of paragnathi; IV a semilunar group, consisting of five rows of densely crowded paragnathi; III three transverse groups, consisting of two or three separate rows of paragnathi; basal region: V absent; VI a small distiohous patch; VII and VIII five, transverse, distichous or tristichous acervuli. In some specimens group II of the maxillary region is absent or only faintly developed. In the anterior body-region


Careful tuning of the learning rate, or even schedules thereof, can be crucial to effective neural net training. There has been much recent interest in gradient-based meta-optimization, where one tunes hyperparameters, or even learns an optimizer, in order to minimize the expected loss when the training procedure is unrolled. But because the training procedure must be unrolled thousands of times, the meta-objective must be defined with an orders-of-magnitude shorter time horizon than is typical for neural net training. We show that such short-horizon meta-objectives cause a serious bias towards small step sizes, an effect we term short-horizon bias. We introduce a toy problem, a noisy quadratic cost function, on which we analyze short-horizon bias by deriving and comparing the optimal schedules for short and long time horizons. We then run meta-optimization experiments (both offline and online) on standard benchmark datasets, showing that meta-optimization chooses too small a learning rate by multiple orders of magnitude, even when run with a moderately long time horizon (100 steps) typical of work in the area. We believe short-horizon bias is a fundamental problem that needs to be addressed if meta-optimization is to scale to practical neural net training regimes.


Higher Education institutions worldwide are aware of the fact that intercultural and interdisciplinary collaborations will be an essential part of their students' professional lives. To that effect, it is crucial to develop pedagogical strategies to provide students with the skills that will give them the mobility and flexibility to operate efficiently in different cultural contexts. 'Reading Across Cultures' is a module taught at Monash University that was specifically designed to enhance students' levels of Cultural Literacy. The module is particularly innovative in that its structure follows that of a literary studies course, but it focuses on teaching students how to transfer the analytical and interpretative skills learnt in the classroom to real life scenarios. This article presents a detailed description of how 'Reading Across Cultures' does this. In the context of Localization and Internationalization Studies, the article discusses the need to teach our students how to 'localize themselves', and how this can be achieved by means of Cultural Literacy. It also provides an explanation of the overall structure of 'Reading Across Cultures', including a description of assignments that will be particularly useful for educators at a tertiary level who seek to plan similar courses aimed at enhancing students' levels of Cultural Literacy or Intercultural Competence. The article focuses on two specific techniques that were used throughout the module to enhance students' levels of Cultural Literacy: 'destabilization' and 'reflection'.


A rostrocaudal (RCd) nasal view was developed in large breed mesaticephalic dogs using a complete, subsequently sectioned, skull and cadaver specimens to optimise the radiographic technique and evaluate normal anatomic features. Gelatin was placed in one nasal passage of the cadaver specimens to mimic the effects of nasal pathology. The latter specimens and 18 clinical cases with suspected nasal disease were evaluated to determine the usefulness of the RCd view compared to standard nasal views. An optimal RCd view was obtained with the dog in dorsal recumbency and the head symmetrically positioned with the hard palate perpendicular to the table using a table top technique with 8:1 grid, collimating to the nasal region and centring the primary beam on the philtrum. The dorsolateral aspects of the maxillary bone, the nasal bones, septal sulcus of the vomer, mucosa lined nasal septum and conchae could be seen. A centrodorsal more radiolucent area representing the ethmoid bone region was also visible. Gelatin soft tissue opacification of the nasal passage could be seen more clearly in RCd nasal view than in occlusal dorsoventral view. In clinical cases the RCd view was useful to build up a 3-dimensional image of nasal passage pathology as well as to detect nasal septum and osseous nasal border pathology not visible in other views. This view is particularly useful in cases where cross-sectional imaging modalities are not available or where the nasal investigation is limited by cost considerations.


The purpose of this study was to investigate the effects of computerized and traditional ear training methods on the aural skills abilities of elementary music students. The sample consisted of 20 students who were randomly assigned to either an experimental or control group. The experimental group was taught for five sessions using computerized ear training program while the control group was taught for five sessions using traditional, non-computerized ear training methods. At the end of the five sessions, students were tested. Data were collected by administering a test to both experimental and control groups that measured students' ability to identify by ear eleven different pitch intervals and three different qualities of chords. Students were also administered a survey to measure their attitudes toward their experience in the ear training program. Data were analyzed using independent t-tests. The results indicated a significant difference between the test scores of the control and experimental groups. There was no significant difference found between the experimental and control groups regarding their attitude survey results. The results of this study suggest the use of computerized ear training instruction is beneficial in achieving aural skills.


Developing and maintaining a consistent brand statement is an important aspect of developing a successful product. However, maintaining that statement is difficult due in part to the inconsistent and often insufficient understanding of brand by marketing, engineering, and design. This paper presents shape grammars as a method for encoding the key elements of a brand into a repeatable language, which can be used to generate products consistent with the brand. A detailed investigation into the history of Buick styling reveals the brand characteristics of the front view of Buick vehicles, which are then captured in a shape grammar.Copyright © 2002 by ASME


Numerous shore displacement studies have been completed in Finland, but the shore displacement history regarding the last four millennia is still poorly investigated. In this study, the shore displacement history of the coastal area of Western Uusimaa, in southern Finland, is reconstructed especially for the period 500 BC-AD1500. The isolation of 17 basins located in five areas (Kirkkonummi/Espoo, Orslandet (Inga), Algo (Ekenas in Raseborg), Tenala (Raseborg) and Prastkulla (Ekenas, Raseborg)) is determined. The methods include lithostratigraphic interpretation, diatom analyses and radiocarbon dating. The shore displacement history varies within the Western Uusimaa area. The highest ancient shoreline representing sea-level at 500 BC is about 8.5 m above present sea-level (a.s.l.) in Prastkulla, and 6.5 m a.s.l. in Kirkkonummi. In other areas, the shoreline representing this time falls between these elevations. The shoreline representing sea-level at AD 500 is 1-1.5 m a.s.l. in Western Uusimaa. These differences in shore level elevations are due to differences in isostatic uplift rates, which are slower in the east. The main trend in relative shore displacement along the southern coast of Finland is characterised by a generally decreasing uplift rate during the last 3500 years. I is not possible to detect any clear sea-level transgressions during this investigated period. The available data suggests possible local land uplift anomalies in the study area, but more investigations are needed to verify these results.


Even social systems theory seems somewhat reluctant to call the university a system and treat it as such. Talcott Parsons and Gerald M. Platt called it a bank of intelligence and influence, Niklas Luhmann an organized institution, if not milieu, and Rudolf Stichweh a form, as if it defied any unit closure, let alone double closure concomitant with calling it a system. Even aspects of social system concerning communication within universities or individual and collective action are usually dealt with rather timidly. The main reference for the analysis of universities in social systems theory is the wider society, which defines what functions and structures a university may rely on when producing and reproducing itself. If this is a perfect example of systems theory as a theory of the production and reproduction of a system within an environment, focusing as much on the environment as on the system, there is nevertheless a certain lack when we look at the operation, regulation, autopoiesis, and possible complexity of the university in the terms for which systems theory is famous. How exactly are we to conceive of the self-reference and the other-reference of universities? What are we looking at if we consider the university an example of double closure like any other social system? Would we be able to spell out the complexity of the university depending on an appropriate notion of complexity?


British Liberal Henry Peter Brougham said in the 19th century, "Education makes a people easy to lead, but difficult to drive; easy to govern but impossible to enslave." For decades, Saddam Hussein perverted this philosophy and exploited education as an instrument to maintain his government's iron grip on power in Iraq. Now, in an attempt to revive Brougham's pedagogical ideal, the United States hopes to make education the key to stable democratization in postwar Iraq. [ILLUSTRATION OMITTED] The state of Iraq's school system is a microcosm of the state of Iraqi society during and after the rule of Hussein. For decades, Iraqi schoolbooks were replete with references to Hussein and schoolteachers served as trumpeters of government propaganda. Now, after the US-led war in Iraq, the school system is in shambles with looted school buildings, underpaid (and often under qualified) teachers, and a deadened 30-year-old curriculum. The United States has already begun an effort to reform the education system by purging school texts of all Hussein and Baath party references and bringing education experts from US school systems to serve as advisers in Iraq. Nevertheless, just as Brougham distinguished between "leading" and "driving," the United States must be vigilant in maintaining the distinction between liberation and occupation of Iraq's educational institution. If the United States sees Iraqi education as merely a means for "winning the heart" of the Iraqi people, any changes to the Iraqi school system are likely to be superficial--cleansing schools of Hussein's domineering presence, renovating Iraqi school buildings, and Westernizing the Iraqi curriculum by incorporating democratic values. The stabilization of Iraqi society hinges on the fundamental restructuring and improvement of its education system. Before pursuing democratization, the United States should focus on securing the stability of Iraqi schools as a means of empowering the Iraqi people with the capacity to recreate their own society. Emerging from a Troubled Past When Hussein and the Baath party rose to power in the 1970s, the Iraqi education system became one of indoctrination. The clearest proof, by far, is found in the textbooks written during the period. According to a report by USA Today on October 2, 2003, a fifth grade Iraqi history textbook describes the 1991 Gulf War as "the Mother of all Battles launched by American and Zionist aggression and 30 nations." In mathematics during Hussein's rule, students learned multiplication tables by calculating the casualty count of shooting down four planes with three US pilots in each plane. Students were required to respond to the entrance of an adult in the classroom with "Long live the leader, Saddam Hussein," and began their school day by chanting against the United States for killing Iraqi children and burning Iraqi trees. In physical education classes, students exercised while reciting, "Bush, Bush, listen clearly: We all love Saddam." During flag-raising ceremonies, a teacher fired a round of blanks from an AK-47 rifle to the Hussein chants of students. According to a New York Times article on October 1, 2003, an elementary school teacher at the Tigris School for Girls in Baghdad said of Hussein, "We had to include him in every lesson plan or we'd be in trouble with the Baath Party." After the US-led war in Iraq ousted Hussein, the United States honed in on the domineering presence of Hussein in Iraqi education and rushed to give the schools a "facelift" before four million Iraqi children returned to school in October 2003. The Governing Council, which consists of 25 members appointed by the United States, decreed a purge of all references to Hussein from the education system. Under a project funded by the US Agency for International Development (USAID), Iraqi officials and teachers tore out images of the former Iraqi ruler and crossed out references to him and the Baath party in millions of textbooks. …


How should comparative law scholars engage with other disciplines? Which social sciences are relevant for the purpose of comparison? Such questions are important for the process of comparison, as disciplinary self-regulation (and interaction between disciplines) is not a neutral and objective process, and is always informed by embedded political, ideological, ethical preferences. Or, the act of selecting ways of reading, thinking and writing in the service of any task requires the explicit or implicit endorsement of epistemic and hermeneutic authority. In this essay, I review three recent volumes on comparative law – a companion volume, a book of practice-oriented reflections by scholars who engage in comparative legal scholarship, and a region-specific contribution on Comparative Constitutionalism in South Asia. The approaches adopted in the volumes – concentrating on the science of comparative law, finding a middle way between too much complexity and too little, concentrating on region-specific complexities – do not address the issue of negotiating epistemic and hermeneutic authority posed above. Such negotiation may be facilitated by concentrating on what I suggest is the organising principle of the discipline of comparative law: identifying the construction, perpetuation and functionality of the internal authority of law.


The HL-LHC phase is designed to increase by an order of magnitude the amount of data to be collected by the LHC experiments. To achieve this goal in a reasonable time scale the instantaneous luminosity would also increase by an order of magnitude up to 6 · 1034 cm−2s−1. The region of the forward muon spectrometer (|η| > 1.6) is not equipped with RPC stations. The increase of the expected particles flux up to 2 kHz/cm2 (including a safety factor 3) motivates the installation of RPC chambers to guarantee redundancy with the CSC chambers already present. The current CMS RPC technology cannot sustain the expected background level. The new technology that will be chosen should have a high rate capability and provide a good spatial and timing resolution. A new generation of Glass-RPC (GRPC) using low-resistivity glass is proposed to equip at least the two most far away of the four high η muon stations of CMS. First the design of small size prototypes and studies of their performance in high-rate particles flux are presented. Then the proposed designs for large size chambers and their fast-timing electronic readout are examined and preliminary results are provided.


Praise for Practical Malware Analysis The book every malware analyst should keep handy. --Richard Bejtlich, CSO, Mandiant & Founder of TaoSecurity An excellent crash course in malware analysis. --Dino Dai Zovi, Independent Security Consultant . . . the most comprehensive guide to analysis of malware, offering detailed coverage of all the essential skills required to understand the specific challenges presented by modern malware. --Chris Eagle, Senior Lecturer of Computer Science at the Naval Postgraduate School A hands-on introduction to malware analysis. I'd recommend it to anyone who wants to dissect Windows malware. --Ilfak Guilfanov, Creator of IDA Pro . . . a great introduction to malware analysis. All chapters contain detailed technical explanations and hands-on lab exercises to get you immediate exposure to real malware. --Sebastian Porst, Google Software Engineer . . . brings reverse engineering to readers of all skill levels. Technically rich and accessible, the labs will lead you to a deeper understanding of the art and science of reverse engineering. I strongly recommend this book for beginners and experts alike. --Danny Quist, PhD, Founder of Offensive Computing If you only read one malware book or are looking to break into the world of malware analysis, this is the book to get. --Patrick Engbretson, IA Professor at Dakota State University and Author of The Basics of Hacking and Pen Testing . . . an excellent addition to the course materials for an advanced graduate level course on Software Security or Intrusion Detection Systems. The labs are especially useful to students in teaching the methods to reverse engineer, analyze and understand malicious software. --Sal Stolfo, Professor, Columbia University


We present the result of searches for gravitational waves from 200 pulsars using data from the first observing run of the Advanced LIGO detectors. We find no significant evidence for a gravitational-wave signal from any of these pulsars, but we are able to set the most constraining upper limits yet on their gravitational-wave amplitudes and ellipticities. For eight of these pulsars, our upper limits give bounds that are improvements over the indirect spin-down limit values. For another 32, we are within a factor of 10 of the spin-down limit, and it is likely that some of these will be reachable in future runs of the advanced detector. Taken as a whole, these new results improve on previous limits by more than a factor of two.


All My Mothers came to me as the story of a child trying to grasp the cruelty of the world through understanding her murdered mother and, later, her extended family of mothers. When I decided to add chapters from the mother's point of view, I realized that she had the same struggle and so I wanted to parallel their journeys—the journey of a mother and daughter, or two daughters, really—in order to show the way that this family passes on its pain. All this takes place in what J. R. R. Tolkien called a secondary world, a term that we still use to describe fantasy that takes place in a world other than this one. The depth of worldbuilding that comes with this speculative genre places power in the writer's hands to imagine radically feminist worlds or examine power, structures, and beliefs. I also knew I wanted to create societies and characters that are queer. Science fiction and fantasy are uniquely positioned to explore different relationship structures and ways of loving as depicted in feminist classics like Ursula K. LeGuin's The Left Hand of Darkness or Octavia Butler's Dawn. In my novel, all three immortal peoples are ace, agender or genderfluid, and reproduce asexually. While race is not constructed the same way in this world, most of the immortals have shades of dark skin because I think it is powerful to imagine BIPOC as ageless beings with the agency to shape their futures. Given the story's themes of creation, destruction, and environmental apocalypse, I think it's important to see queer femmes saving their worlds, healing their families, and building alliances.


This paper presents an empirical study investigating the use of instant online feedback on face-to-face presentations. This innovative way of using information technology for the specific communication purpose of giving feedback was researched in the context of a university course on "Human-Computer Interaction and Psychology". A total sum of 80 students majoring in Computer Science participated in the instant online feedback activity and 907 feedbacks were given. 72 students returned the questionnaire for evaluating this educational scenario. Quantitative and qualitative analysis revealed that students seem to prefer giving feedback online in addition to a face-to-face setting for reasons like possible anonymity and more honesty. Study results further demonstrate that instant online feedback may facilitate students' interest in and commitment to their presentations, finally also increasing their contributions' quality.


Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, the docking scores are not sufficiently precise to represent the protein-ligand binding affinity. Here, we developed an efficient computational method for calculating protein-ligand binding affinity, which is based on molecular mechanics generalized Born/surface area (MM-GBSA) calculations and Jarzynski identity. Jarzynski identity is an exact relation between free energy differences and the work done through non-equilibrium process, and MM-GBSA is a semimacroscopic approach to calculate the potential energy. To calculate the work distribution when a ligand is pulled out of its binding site, multiple protein-ligand conformations are randomly generated as an alternative to performing an explicit single-molecule pulling simulation. We assessed the new method, multiple random conformation/MM-GBSA (MRC-MMGBSA), by evaluating ligand-binding affinities (scores) for four target proteins, and comparing these scores with experimental data. The calculated scores were qualitatively in good agreement with the experimental binding affinities, and the optimal docking structure could be determined by ranking the scores of the multiple docking poses obtained by the molecular docking process. Furthermore, the scores showed a strong linear response to experimental binding free energies, so that the free energy difference of the ligand binding (ΔΔG) could be calculated by linear scaling of the scores. The error of calculated ΔΔG was within ≈±1.5 kcal•mol−1 of the experimental values. Particularly, in the case of flexible target proteins, the MRC-MMGBSA scores were more effective in ranking ligands than those generated by the MM-GBSA method using a single protein-ligand conformation. The results suggest that, owing to its lower computational costs and greater accuracy, the MRC-MMGBSA offers efficient means to rank the ligands, in the post-docking process, according to their binding affinities, and to compare these directly with the experimental values.


Chicken Anemia Virus (CAV) is a small spherical negative single stranded
DNA virus which comprised of several overlapping open reading frames (ORPs),
three of which encoded for the proteins size of 52, 24 and 13 kDa, designated as
VPl, VP2 and VP3, respectively. The recombinant Lactococcus lactis AM3 used in
the study was transformed with a plasmid expression vector, pMG36e, which was
cloned with the VP3 gene of CAV. This recombinant Lactococcus lactis AM3 was
constructed as a model to study the possibility of vaccine delivery into the poultry
via oral route. The investigation on the growth of the recombinant Lactococcus lactis
AM3 in different carbon sources (glucose, sucrose, lactose and xylose) showed that glucose was the most suitable carbon source where it successfully produced 36;
generation numbers of bacteria with final plasmid-bearing cells, 1.13 X 1017 cfu.L⁻¹
after 24 hours of fermentation. The final plasmid stability of recombinant
Lactococcus lactis AM3 grew in the glucose medium was 98% indicating that most
of the recombinant bacterial still retained their plasmids. There was a stable and
optimum growth of the recombinant Lactococcus lactis AM3 in the culture medium
with 10 g.L⁻¹ of glucose concentration. The maximum'specific growth rate of
plasmid-bearing cells in the culture, .µMAXpb was 0.9885h⁻¹. The higher concentration
of glucose (20, 40 and 60 g.L⁻¹) in the medium inhibited the growth of recombinant
Lactococcus lactis AM3 . The specific growth rate of Lactococcus lactis AM3 grew
in the medium with 20 g.L⁻¹ of yeast extract was the highest, 0.8869 h⁻¹ with 84% of
plasmid stability. Similar polypeptides average molecular weights are observed in
the yeast extract medium that increased the nitrogen consumption by the
recombinant bacteria and eventually increased the bacteria cell number.
Further experiments confirmed that 20 g.L⁻¹ of glucose and 20 g.L-1 of yeast
extract containing medium was the optimum carbon-nitrogen source for the growth
and plasmid maintenance of the recombinant Lactococcus lactis AM3. The specific
growth rate and plasmid stability of Lactococcus lactis AM3 in this complex
medium were increased to 1.6304 h⁻¹ and 87%, respectively after 26 hours of batch
fermentation. There was no nitrogen deficiency occurred and the lost of plasmid,
pMG36e-VP3 from the host cell was caused majority by the segregational instability
of plasmid after prolonged fermentation. The specific growth rate of recombinant Lactococcus lactis AM3 grew at pH
medium 6.5 was the highest, 1.0227 h⁻¹. 91% of plasmid stability of recombinant
Lactococcus lactis AM3 grew at pH 6.5 was observed. The maximum specific
growth rate of Lactococcus lactis AM3 grew at 30‹C was 0.9780 h⁻¹ with total
plasmid-bearing cells of 9.80 X 1020 cfu.L⁻¹ after 28 hours of fermentation. Similar
acid-inducible proteins were produced by recombinant Lactococcus lactis AM3
when confronted with high temperatures (32, 34, 36 and 38˚c%). 90% of plasmid
stability was observed in Lactococcus lactis AM3 grew at 30‹C. Recombinant
Lactococcus iactis AM3 grew in the MRS medium that agitated with 200 r.p.rn.
produced 32 generations of plasmid..bearing cells, 3.87 X 1 019 cfu.L⁻¹ with 51% of
plasmid stability after 26 hours of fermentation.
Obvious fluctuation of the plasmid stability of pMG36e- VP3-bearing cells
was observed during the batch fermentation system. The appearance of adaptive
descendants without plasmids derived from the bacterial host cells was detected
throughout the experiments. The lost of plasmid, pMG36e- VP3 from recombinant
Lactococcus lactis AM3 and the fluctuations in the population of plasmid..losing
cells in the batch fermentation system suggested that the presence of antibioticdegraded
proteins or acids were produced from the bacterial host cells that
responsible in the inhibition of proper function of erythromycin in the culture. Most
of the plasmid instability was caused by segregational instability.


Cloud computing offers a model where resources (storage, applications, etc.) are abstracted and provided "as-a-service" in a remotely accessible manner. In such a service-based environment, the Cloud provisioning relies on stipulated Service Level Agreements (SLAs). Such an agreement is a contract between the Cloud Service Provider (CSP) and the Cloud Service Customer (CSC) regarding the offered services. These SLAs specify the Cloud services requested by the customers and are required to be achieved by the CSPs. A variety of parameters for different aspects of a service can be included in the SLA, such as but not limited to: availability, performance, downtime and location of the data.

Although there are numerous claimed benefits of the Cloud to ensure confidentiality, integrity, and availability of the stored data, the number of security breaches is still on the rise. The lack of security assurance and transparency prevented customers/enterprises from trusting the CSPs, and hence not using their services. Unless the customer's security requirements are identified and documented by the CSPs, customers can not be assured that the CSPs will satisfy their requirements. Although the recent efforts on specification of security services using SLAs, also known as security SLAs or secSLAs, is a positive development, multiple technical and usability issues limit the adoption of Cloud secSLAs in practice.

For example, multiple CSPs offer similar security services (e.g., "encryption key management") albeit with different capabilities and prices. The customers need to comparatively assess the offered security services in order to select the best CSP matching their security requirements. However, the presence of both explicit and implicit dependencies across security related services add further challenges for Cloud customers to: (i) specify their security requirements taking service dependencies into consideration, (ii) determine which CSP can satisfy these requirements in a qualitative way, and (iii) identify threats that can compromise their data ownership requirements of security, functionality and performance.

Although secSLA provides specifications for the security level to be provided, assurance mechanisms are required to validate the compliance of the enforced security mechanisms to the secSLA. The lack of security transparency on the security controls implemented in the Cloud and the diversity of the security specifications covered in the secSLA make validating the service to the secSLA a challenging task. Furthermore, the customer's compensation upon a violation is a manual time intensive process.

Finally, despite the benefits of enclosing security-related information in the secSLAs, CSPs are hesitant to release detailed information regarding their security posture for security and proprietary reasons. This lack of security transparency makes assessing and validating the offered security level and finding the best CSP matching the customer's security requirements a challenging task.

In this dissertation we address the aforementioned challenges. For challenges (i) and (ii), two evaluation techniques for conducting the quantitative assessment and analysis of the secSLA-based security level provided by CSPs with respect to a set of Cloud customer security requirements are presented. The proposed techniques help to improve the security requirements' specifications by introducing a flexible and simple methodology that allows customers to identify and represent their specific, imprecise and inconsistent security needs. The techniques automatically detect conflicts resulting from inconsistent customer requirements and provide an explanation for the detected conflicts which in-turn allows customers to resolve these conflicts. To tackle challenge (iii) and uncover threats that can compromise the customer's data ownership requirements, a threat analysis process is presented which establishes the viability of identifying threats based on the CSPs' offered services and customers' requirements.

To validate the compliance of CSPs to the contracted services in the secSLA(s), a decentralized customer-based monitoring approach is proposed. The monitoring approach detects secSLA's violations and autonomously compensates customers according to the violation severity. The approach relies on the Ethereum blockchain to securely store monitoring logs and incorporate secSLAs as smart contracts. The compliance validation framework is implemented and its functionality is evaluated on Amazon EC2.

Finally, a system that enables (a) CSPs to disclose detailed information about their offered security services in an encrypted form to ensure data confidentiality, and (b) customers to assess the CSPs' offered security services and find those satisfying their security requirements is presented. The system preserves each party's privacy by leveraging an evaluation method based on secure two-party computation and searchable encryption techniques. The system is implemented and evaluated by applying it to existing standardized secSLAs. We show that the system's performance is practical for the presented use-case. The system is formally proved against a strong realistic adversarial model, using an automated cryptographic protocol verifier.


There is a lack of substantial data on changes in calciotropic hormones and bone markers in elderly subjects living in North America. Parathyroid hormone (PTH), serum 25‐hydroxyvitamin D (25(OH)D) and bone markers (serum osteocalcin and urine N‐telopeptide), were measured in 735 Caucasian subjects (235 men and 500 women) aged 65–87 years. There was a significant increase in serum osteocalcin and urine N‐telopeptide with age in men, and a significant increase in serum osteocalcin with age in women. Serum PTH and 25(OH)D showed no significant change with age in men or women. After adjusting for age, calcium intake, serum creatinine, season, and weight, mean serum PTH (p = 0.01), serum osteocalcin (p = 0.0001) and 24 h urine N‐telopeptide (p = 0.0001) were higher in women than men, and mean serum 25(OH)D (p = 0.0001) and 24 h urine calcium (p = 0.0001) were higher in men than women. Serum PTH was correlated with serum osteocalcin in men and women, r = 0.24, r = 0.17, p < 0.001, but not with urine N‐telopeptide. Serum PTH was inversely correlated with serum 25(OH)D (r = −0.25, r = −0.34, p < 0.001), and positively correlated with serum creatinine (r = 0.14, r = 0.17, p < 0.01) in men and women. The prevalence of serum 25(OH)D levels below 12 ng/ml was only 3.3% in females and 0.4% in men. Thus vitamin D deficiency was very uncommon in the U.S.A. compared with Europe. Although mean serum PTH was increased in the elderly, only 4–6% had PTH levels above the normal range. In summary, the increase in serum PTH in the elderly can be explained more by changes in vitamin D status than by declining renal function. These data also show significantly higher (p = 0.001) bone remodeling markers in women.


Living cells accumulate compensatory solutes for protection against the harmful effects of extreme environmental conditions such as high salinity, temperature and desiccation. Even at high concentrations these solutes do not disrupt the normal cellular functions and at times counteract by stabilizing the cellular components. These properties of compensatory solutes have been exploited for stabilizing proteins and cells in vitro. Betaines are widespread natural compensatory solutes that have also been used in other applications such as therapeutic agents and polymerase chain reaction (PCR) enhancers. Some biomedical applications of novel synthetic analogues of natural betaines were investigated. Natural compensatory solutes are either dipolar zwitterionic compounds or polyhydroxyl compounds, and the physical basis of compensation may differ between these, so one focus was on synthetic betaines with hydroxyl substituents. The majority of the synthetic solutes stabilized different model proteins against stress factors such as high and low temperatures. The presence of hydroxyl groups improved protection against desiccation. The observed stabilization effect is not just on the catalytic activity of the enzyme, but also on its structural conformation. Synthetic compensatory solutes have a potential application as protein stabilizers. Dimethylthetin was evaluated as a therapeutic agent and found to be harmful in a sheep model. However, from the study we were able to generate a large-animal continuous ambulatory peritoneal dialysis (CAPD) model and showed that glycine betaine could be added to the dialysis fluid in chronic renal failure. Some synthetic compensatory solutes reduce the melting temperatures of DNA better than most natural solutes. Synthetic solutes were identified that have potential to enhance PCR and could replace some reagents marketed by commercial suppliers. Density, viscosity and molecular model data on the solutes showed correlations with the biochemical effects of the solutes, but no physical measurements were found that reliably predicted their potential for biotechnological applications.


Background: Allergic rhinitis, a chronic inflammatory disease of the upper airways, has a major effect on the life quality of patients. The inflammatory response in the nasal mucosa includes an immediate IgE-mediated response by mast cell, so that the late phase of response is characterized by recruitment of eosinophilsand basophils. IL-18 is a member of the IL-1 family and originally is described as an IFN-γ –inducing factor (IGIF), also it is known for influencing the balance of Th1/Th2 immune response. The aim of this study to investigated that whether immunoglobulin (Ig) E levels in serum are associated with allergic rhinitis.
Materials and Methods: Genotyping for -137G/C SNPs of IL18 promoter was performed using 130 patients with AR and 62 healthy control volunteers then serum levels of total IgE were determined by ELISA method. Statistical analyses were carried out by use of SPSS version 19.
Results: The results showed that no significant relationship between genotypes -137G / C polymorphism and serum IgE levels between patients and controls in allergic rhinitis (P> 0.05).
Conclusion: According to the results of this study, it seems that the IL18 gene polymorphism -137G/C is not associated with IgE levels and susceptibility of allergic rhinitis.
Keywords: Allergic rhinitis, (Interleukin-18) IL-18, Polymorphism, IgE.


The status of the Lophophorates is one of the central problems of current zoology. There is a contradiction between the molecular results, which mainly indicate the polyphyly of the lophophorates, and morphological results, which indicate the monophyly of the lophophorates. An understanding of lophophore innervation can help answer question about the status of the lophophorates. Data on the lophophore innervation, which were obtained by methods of immunocytochemistry, transmission electron microscopy, and laser confocal scanning microscopy in species from all three groups of the lophophorates, are summarized in this report. According to morphological results, the lophophore has several main nerves that seem to be homologous among different lophophorates. The main brachial nerve of brachiopods is homologous to the dorsal ganglion of phoronids and to the cerebral ganglion of ectoprocts. The accessory brachial nerve of brachiopods is homologous to the minor nerve ring of juvenile phoronids and to the circum oral nerve of ectoprocts. The lower brachial nerve of brachiopods is homologous to the tentacular nerve ring of phoronids and to the outer nerve of ctenostome ectoprocts. Morphological data on the lophophore innervation indicate that the Lophophorata is monophyletic group including three phyla: Phoronida, Brachiopoda, and Bryozoa. Contradiction between morphological and molecular results might be explained by of bryozoans, whose evolution was associated with great morphological and, apparently, molecular changes. To reject the lophophorates monophyly we should suggest the independent origin of the lophophore — a specific tentacular structure having specific innervation — in both Bryozoa and Brachiozoa (= Phoronida + Brachiopoda). How to cite this article: Temereva E.N. 2017. Morphology evidences the lophophorates monophyly: brief review of studies on the lophophore innervation // Invert. Zool. Vol.14. No.1. P.85–91. doi: 10.15298/invertzool.14.1.12


Background: Although early detection and screening for colorectal cancer saves lives, screening rates remain suboptimal, especially for minorities, underserved populations, older adults (>60), men, un/under insured, and those living in rural settings. The goal of the colorectal cancer education and screening program is to target the un- or under- insured in a 19-county primarily rural target area to provide: 1) education concerning CRC and CRC screening to 12,000 individuals, and 2) CRC screenings (colonoscopy and/or FIT) to 5,1613 un- or under- insured individuals. Methods: The education outreach team targets local health fairs, clinics, churches, etc. to educate individuals on CRC and the importance of screening. The program aims to then have those individuals electively undergo a colonoscopy and/or a FIT test. The number of those educated and screened is recorded. The results related to colonoscopy, FIT, and follow-up are collected. Results: Primary outcomes include number of individuals educated, number of FIT test/colonoscopies performed and results of screening procedures. Conclusions: This education and screening outreach program is designed to reach primarily rural and underserved populations eligible for colorectal screening. Results of efficacy of program will advance knowledge on how to conduct colorectal cancer outreach programs in rural settings.


Natural flow regimes represent the hydrologic conditions to which native aquatic organisms are best adapted. We completed a regional river classification and quantitative descriptions of each natural flow regime for the Ozark–Ouachita Interior Highlands region of Arkansas, Missouri and Oklahoma. On the basis of daily flow records from 64 reference streams, seven natural flow regimes were identified with mixture model cluster analysis: Groundwater Stable, Groundwater, Groundwater Flashy, Perennial Runoff, Runoff Flashy, Intermittent Runoff and Intermittent Flashy. Sets of flow metrics were selected that best quantified nine ecologically important components of these natural flow regimes. An uncertainty analysis was performed to avoid selecting metrics strongly affected by measurement uncertainty that can result from short periods of record. Measurement uncertainties (bias, precision and accuracy) were assessed for 170 commonly used flow metrics. The ranges of variability expected for select flow metrics under natural conditions were quantified for each flow regime to provide a reference for future assessments of hydrologic alteration. A random forest model was used to predict the natural flow regimes of all stream segments in the study area based on climate and catchment characteristics, and a map was produced. The geographic distribution of flow regimes suggested distinct ecohydrological regions that may be useful for conservation planning. This project provides a hydrologic foundation for future examination of flow–ecology relationships in the region. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.


The Country Opinion Survey in Peru assists the World Bank Group (WBG) in gaining a better understanding of how stakeholders in Peru perceive the WBG. It provides the WBG with systematic feedback from national and local governments, multilateral/bilateral agencies, media, academia, the private sector, and civil society in Peru on 1) their views regarding the general environment in Peru; 2) their overall attitudes toward the WBG in Peru; 3) overall impressions of the WBG's effectiveness and results, knowledge work and activities, and communication and information sharing in Peru; and 4) their perceptions of the WBG's future role in Peru.


The tropomyosin-related kinase (Trk) family consists of three receptor tyrosine kinases (RTKs) called TrkA, TrkB, and TrkC. These RTKs are regulated by the neurotrophins, a class of secreted growth factors responsible for the development and function of neurons. Given the high homology between the Trks and their use of overlapping signaling pathways, the key question to be addressed is how the activation of the different Trks can lead to distinct cellular outcomes. To this end, I first sought to determine the mechanism of autoregulation for the Trk tyrosine kinase domain (TKD). The Trk TKDs are members of the insulin receptor kinase (IRK) superfamily and recent data suggest that the IRK family displays a wide array of autoinhibitory mechanisms. To determine where TrkA and the closely related Ror2 TKD (from an unconventional Wnt receptor) lie in this spectrum, we determined the crystal structures of the kinase domains of these RTKs. In both cases, the conformation of the activation loop resembles the IRK activation loop conformation, with subtle but notable differences in the case of Ror2. These findings aid in understanding the range of autoinhibitory mechanisms of the IRK family, in addition to providing a foundation for deciphering consequences of TKD mutations in this family. I also observed crystallographic dimers of the inactive TrkA TKD that resemble those seen for other RTK TKDs which may aid in understanding the reported preformed inactive TrkA dimers observed in cells. To understand the molecular basis for differences in signaling specificity of the Trk receptors, I investigated whether the TrkA and TrkB TKDs differ in their intrinsic kinase activities. I show that the TrkA TKD autophosphorylates itself faster than its TrkB counterpart. However, this difference of autophosphorylation is not due to a difference in kinase activity per se. Rather, my data indicate that the difference in autophosphorylation may arise because of self-association of the TrkA TKD that does not occur with TrkB. My work sheds light on potential differences between TrkA and TrkB signaling, as well as providing a quantitative understanding of Trk TKD activation, which is useful for effective and selective inhibitor design. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Biochemistry & Molecular Biophysics First Advisor Mark A. Lemmon


Abstract. The characteristic cross-tail width of bursty bulk flows (BBFs) in earth's plasma sheet was investigated at two stages of its life, one at its onset, the other when it is fully developed. Equilibrium domains with gradient of magnetic field are constructed. Interchange instability analysis of such domains yields the most unstable mode with the half wave length comparable with the observed cross-tail width of a flow burst and the inverse of growth rate comparable with its duration. The thickness of the plasma sheet for the most unstable mode is also comparable to the width of BBFs in the north–south direction. We found that viscosity, the dimension of the unstable domain, the thickness of the plasma sheet and gradient of the magnetic field together determine the most unstable mode. The ion Larmor radius plays an important role in viscosity as half effective mean free path. For a fully developed flow, however, velocity-caused pressure difference between the leading and trailing sides of a flow burst also plays a role. The equatorial cross section of flow is reshaped and its cross-tail width is changed as well. Representing the surrounding medium with empirical magnetic field and plasma models, the force balance of the fast flow is analyzed. The cross-section area of flow burst is estimated to be one to several square earth radii, and the cross-tail width of fast flow is estimated to be 1 to 3 earth radii, which is consistent with observations of BBFs.


Abstract Ontario Power Generation Nuclear (OPGN) has a 4 x 880 MWe CANDU nuclear station at its Darlington Nuclear Division located in Bowmanville. The station operates a Tritium Removal Facility (TRF) to reduce and maintain low tritium levels in the Moderator and Heat Transport heavy water systems of Ontario's CANDU fleet by extracting, concentrating, immobilizing and storing as a metal tritide. Minimizing tritium releases to the environment is of paramount importance to ensure that dose to the public is as low as reasonably achievable (ALARA) and to maintain credibility with the Public. Tritium is removed from the Cryogenic Distillation System to the Tritium Immobilization System (TIS) glove box via a transfer line that is protected by a rupture disc and relief valve. An overpressure event in 2003 had caused the rupture disc to blow, resulting in the release of a significant quantity of elemental tritium into the relief valve discharge line, which ties into the contaminated exhaust system. As a result of a few similar events occurring over a number of years of TRF operation, the released elemental tritium would have been converted to tritium oxide in the presence of a stagnant moist air environment in the stainless steel discharge line. A significant amount of tritium oxide hold-up in the discharge line was anticipated. To minimize any further releases to the environment, a Bubbler System was designed to remove and recover the tritium from the discharge line. This paper summarizes the results of several Bubbler recovery runs that were made over a period of a month. Approximately 3500 Ci of tritium oxide and 230 Ci of elemental tritium were removed and collected. The tritium contained in the water produced from the Bubbler system was later safely recovered in the station's downgraded D2O clean-up and recovery system.


This paper describes algorithms that allow multiple hierarchical radiosity solvers to work on the same radiosity solution in parallel. We have developed a system based on a group iterative approach that repeatedly: 1) partitions patches into groups, 2) distributes a copy of each group to a slave processor which updates radiosities for all patches in that group, and 3) merges the updates back into a master solution. The primary advantage of this approach is that separate instantiations of a hierarchical radiosity solver can gather radiosity to patches in separate groups in parallel with very little contention or communication overhead. This feature, along with automatic partitioning and dynamic load balancing algorithms, enables our implemented system to achieve significant speedups running on moderate numbers of workstations connected by a local area network. This system has been used to compute the radiosity solution for a very large model representing a five floor building with furniture. CR


Cytosines at cytosine-guanine (CG) dinucleotides are the near-exclusive target of DNA methyltransferases in mammalian genomes. Spontaneous deamination of methylcytosine to thymine makes methylated cytosines unusually susceptible to mutation and consequent depletion. The loci where CG dinucleotides remain relatively enriched, presumably due to their unmethylated status during the germ cell cycle, have been referred to as CpG islands. Currently, CpG islands are solely defined by base compositional criteria, allowing annotation of any sequenced genome. Using a novel bioinformatic approach, we show that CG clusters can be identified as an inherent property of genomic sequence without imposing a base compositional a priori assumption. We also show that the CG clusters co-localize in the human genome with hypomethylated loci and annotated transcription start sites to a greater extent than annotations produced by prior CpG island definitions. Moreover, this new approach allows CG clusters to be identified in a species-specific manner, revealing a degree of orthologous conservation that is not revealed by current base compositional approaches. Finally, our approach is able to identify methylating genomes (such as Takifugu rubripes) that lack CG clustering entirely, in which it is inappropriate to annotate CpG islands or CG clusters.


Self-annihilating or decaying dark matter in the Galactic halo might produce high energy neutrinos detectable with neutrino telescopes. We have conducted a search for such a signal using 276 days of data from the IceCube 22-string configuration detector acquired during 2007 and 2008. The effect of halo model choice in the extracted limit is reduced by performing a search that considers the outer halo region and not the Galactic Center. We constrain any large-scale neutrino anisotropy and are able to set a limit on the dark matter self-annihilation cross section of h similar or equal to 10(-22) cm(3) s(-1) for weakly interacting massive particle masses above 1 TeV, assuming a monochromatic neutrino line spectrum.


A large-scale laminar network model sheds light on frequency-dependent interactions in the primate cortex. Interactions between top-down and bottom-up processes in the cerebral cortex hold the key to understanding attentional processes, predictive coding, executive control, and a gamut of other brain functions. However, the underlying circuit mechanism remains poorly understood and represents a major challenge in neuroscience. We approached this problem using a large-scale computational model of the primate cortex constrained by new directed and weighted connectivity data. In our model, the interplay between feedforward and feedback signaling depends on the cortical laminar structure and involves complex dynamics across multiple (intralaminar, interlaminar, interareal, and whole cortex) scales. The model was tested by reproducing, as well as providing insights into, a wide range of neurophysiological findings about frequency-dependent interactions between visual cortical areas, including the observation that feedforward pathways are associated with enhanced gamma (30 to 70 Hz) oscillations, whereas feedback projections selectively modulate alpha/low-beta (8 to 15 Hz) oscillations. Furthermore, the model reproduces a functional hierarchy based on frequency-dependent Granger causality analysis of interareal signaling, as reported in recent monkey and human experiments, and suggests a mechanism for the observed context-dependent hierarchy dynamics. Together, this work highlights the necessity of multiscale approaches and provides a modeling platform for studies of large-scale brain circuit dynamics and functions.


Leptin is a pleiotropic cytokine‐like hormone that is involved in the regulation of energy intake and expenditure, neuroendocrine function, immunity and lipid and glucose metabolism. The few humans with genetically based leptin deficiency provide a unique model to assess those effects. We have identified five Turkish patients (one male and two female adults; one boy and one girl) with congenital leptin deficiency due to a missense mutation in the leptin gene. Four of these patients were treated with physiological doses of recombinant methionyl human leptin. Body composition, brain structure and function, behaviour, immunity and endocrine and metabolic parameters were evaluated before and during treatment. Our results showed that leptin has peripheral, hypothalamic and extra‐hypothalamic effects. Within the endocrine system, leptin regulates the circadian rhythms of cortisol, thyroid‐stimulating hormone, luteinizing hormone and follicle‐stimulating hormone. In the brain, leptin controls energy balance and body weight, and plays a role on neurogenesis and brain function. Leptin is a key element of the adiposinsular axis, enhances immune response, and regulates inflammation, coagulation, fibrinolysis and platelet aggregation. Our 10‐year experience in treating these unique patients provided valuable data on the peripheral and central effects of leptin. Those results can be taken into account for the development of leptin‐based therapies for other diseases.


The debt crisis of the early 1930s was probably the largest and most widespread in history. The defaults of national and sub-national governments were pivotal events of the Great Depression and contributed to shaping post-World War II finance in the United States and worldwide. I study the role of a so-far largely unexplored factor - fiscal fragility - in the crisis. In order to do this, I construct and analyse a dataset comprising a new measure of default size and new estimates of the size and composition of public debts for around 25 countries. The data accounts for maturity structures, sub-national borrowing as well as other key characteristics of debt burdens. I show econometrically that the severe deterioration in public revenues experienced by national and sub-national governments in a number of countries was a key determinant of the defaults above and beyond the Great Depression income shock. Countries hardest hit by the slump were more likely to renege on their external debts at both the national and subnational level, but countries whose public revenues fell more moderately were able avoid or limit the size of default. I furthermore show that the collapse in public revenues was not part of an explicit strategy to counter the slump through an active fiscal policy. On the contrary, the evidence indicates that fiscally weak countries saw their public expenditures collapse alongside revenues.


Semi-Supervised Learning (SSL) techniques have become very relevant since they require a small set of labeled data. In this scenario, graph-based SSL algorithms provide a powerful framework for modeling manifold structures in high-dimensional spaces and are effective for the propagation of the few initial labels present in training data through the graph. An important step in graph-based SSL methods is the conversion of tabular data into a weighted graph. The graph construction has a key role in the quality of the classification in graph-based methods. Nevertheless, most of the SSL literature focuses on developing label inference algorithms without studying graph construction methods and its effect on the base algorithm performance. This PhD project aims to study this issue and proposes new methods for graph construction from flat data and improves the performance of the graph-based algorithms.


Quartz fabrics from tectonites belonging to the metamorphic sequence of the Los Reales nappe, in the Betic cordillera (SE Spain), provide a fabric zoning which mainly reflects different temperature conditions during plastic deformation. In XZ section the most representative diagrams of quartz c-axes range from pronounced maxima near the stretching lineation in granulitic samples, through maxima over the Y-axes in migmatites, to maxima at high angles to the foliation in the schists. This fabric variation. suggests that (c)-slip was dominant in granulitic rocks whereas a-slip on prismatic and basal planes, respectively, were activated in migmatites and schists


Binding of CD3ε subunits to the plasma membrane shields critical residues from tyrosine kinases, thus preventing inadvertent T cell activation. T cell activation occurs when a T cell receptor (TCR) is exposed to antigen bound to a major histocompatability complex (MHC) on the surface of an antigen-presenting cell. The TCR is noncovalently associated with the δ, ε, γ, and ζ subunits of CD3, which among them contain 10 cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs). Binding of antigen to the TCR triggers the tyrosine phosphorylation of these ITAMs, which results in downstream signaling events, but how ITAM phosphorylation is initiated is unclear. This led Xu et al. to investigate the role of the transmembrane CD3ε subunit in T cell activation. They first showed that a fluorescently labeled peptide corresponding to the cytoplasmic domain of CD3ε (CD3εCD) bound to phospholipid vesicles and that this interaction depended on a segment of basic (positively charged) residues of CD3εCD but not on its ITAM motif. Fluorescence resonance energy transfer (FRET) between labeled CD3ε and the membrane demonstrated that wild-type CD3ε, but not a mutant CD3ε in which six basic residues were mutated to serines, bound to the plasma membrane of a transfected human T cell line. Analysis of the CD3εCD in complex with a phospholipid bicelle structure by nuclear magnetic resonance (NMR) spectroscopy revealed that lipid-binding induced a fold in the structure of the CD3εCD such that its ITAM motif was embedded in the hydrophobic region of the bilayer, which made it inaccessible to the tyrosine kinase Lck in vitro. As Kuhns and Davis discuss, binding of CD3ε to phospholipids in the plasma membrane shields its ITAM from tyrosine kinases, which implies that some other signal, perhaps mechanical, is required to enable ITAM-mediated signaling events to occur upon engagement of the TCR. C. Xu, E. Gagnon, M. E. Call, J. R. Schnell, C. D. Schwieters, C. V. Carman, J. J. Chou, K. W. Wucherpfennig, Regulation of T cell receptor activation by dynamic membrane binding of the CD3ε cytoplasmic tyrosine-based motif. Cell 135, 702–713 (2008). [PubMed] M. S. Kuhns, M. M. Davis, The safety on the TCR trigger. Cell 135, 594–596 (2008). [PubMed]


Over the last two decades a geographically staggered-legalization of marijuana has commenced in the United States. Early-legalizing states may subsequently enjoy a first-mover advantage which will help them stake a long-run foothold in what may evolve into a national market. To gain insight, we examine another geographically-staggered legalization—that of 3.2 percent beer. Between April 1933 and May 1937 every state legalized the production and sale of beer. Indeed we find that those states that legalized beer earlier in this period had more breweries not just in the years immediately following legalization, but also in 1977, just prior to the beginning of the craft brewing movement in the US. This finding holds even when variables related to long-term brewing tradition are held constant.


This article analyzes claims that the Internet is destroying the book publishing, music, and movie industries, and that Internet use needs to be strictly regulated by civil and criminal copyright laws in order to save US companies and jobs. I survey empirical evidence that copyright industry sales and profits have increased, that economic trends other than infringement on the Internet drive fluctuations in music sales, and that the incentives to produce copyrighted work do not respond directly to minor variations in copyright doctrine or to significant new copyright enforcement laws. The article analyzes ten fundamental myths that have been used to justify Internet censorship or draconian copyright reforms. Four of these myths concern the allegedly negative relationship between Internet usage of various kinds and declining profitability or sales at old media firms. Three of the myths are designed to motivate Congress or the courts to endorse restrictions on Internet content using the justification that old media will benefit from such restrictions, thereby creating jobs and economic growth. The final three myths involve false assumptions that criminalizing Internet activity will save old media firms. Among other evidence that is useful to dispel these myths, this article examines: book and audiovisual media consumption in the aggregate; the continued growth of old-media entertainment sales such as books, music transactions, and entertainment subscriptions or admissions despite massive growth in Internet use since 1994; the findings of regression analyses exploring the relationship between Internet file-sharing software use and the music industry's retail sales; socioeconomic trends other than Internet use that may explain changes in the level of music sales in the United States; an empirical disconnect between the level of Internet-based infringement of recording industry copyrights and the level of U.S. record labels' sales; the sales, total employment, profits, and market capitalization of firms in the U.S. film and television sectors in an environment of large-scale Internet-based copyright infringement; survey results suggesting that musicians may not see music file-sharing as having a severe impact on their livelihoods; the effects of copyright term extension on the number of feature films released and the aggregate investment in creating and marketing them in the United States, as well as on the number of films released in Europe; the lack of a correlation between copyright criminalization and subsequent reductions in Internet-based infringement in the United States; and the benefits, if any, of a draconian new copyright-enforcement regime in France from the standpoint of film and music production and sales.


The aquatic environment and drinking water production are under increasing pressure from the presence of pharmaceuticals and their transformation products in surface waters. Demographic developments and climate change result in increasing environmental concentrations, deeming abatement measures necessary. Here, we report on an extensive case study around the river Meuse and its tributaries in the south of The Netherlands. For the first time, concentrations in the tributaries were measured and their apportionment to a drinking water intake downstream were calculated and measured. Large variations, depending on the river discharge were observed. At low discharge, total concentrations up to 40 μg/L were detected, with individual pharmaceuticals exceeding thresholds of toxicological concern and ecological water-quality standards. Several abatement options, like reorganization of wastewater treatment plants (WWTPs), and additional treatment of wastewater or drinking water were evaluated. Abatement at all WWTPs would result in a good chemical and ecological status in the rivers as required by the European Union (EU) Water Framework Directive. Considering long implementation periods and high investment costs, we recommend prioritizing additional treatment at the WWTPs with a high contribution to the environment. If drinking water quality is at risk, temporary treatment solutions in drinking water production can be considered. Pilot plant research proved that ultraviolet (UV) oxidation is a suitable solution for drinking water and wastewater treatment, the latter preferably in combination with effluent organic matter removal. In this way >95% of removal of pharmaceuticals and their transformation products can be achieved, both in drinking water and in wastewater. Application of UV/H2O2, preceded by humic acid removal by ion exchange, will cost about €0.23/m3 treated water.


Modern networks offer end-to-end connectivity however, the increasing amount of traditional offered services may still not fulfill the requirements of ever demanding distributed applications and must therefore be enriched by some form of increased intelligence in the network. This is where the promise of autonomous systems comes into play. Paul Horn of IBM Research first suggested the idea of autonomic computing on October 15, 2001 at the Agenda Conference in Arizona. The need centers around the exponential growth of networking complexity. Autonomous systems are capable of performing activities by taking into account the local environment and adapting to it. No planning is required hence autonomous systems simply have to make the best of the resources at hand. Locality in this scenario is no longer geographical but rather the information and applications on the boundary of the autonomic communicating element, which may be distributed over a wide area. The most common definition of an autonomic computing system is one, which can control the functioning of computer applications and systems without input from the user, in the same way that the autonomic nervous system regulates body systems without conscious input from the individual. Thus, we attempt here to more clearly identify the need for autonomous systems, their architecture, the path of evolution from traditional network elements, and the future of such systems. BACKGROUND


Results of a recent comparative experimental assessment of methods for network community detection applied to benchmark graphs indicate that the two best methods use different objective functions but a similar local search-based optimization (LSO) procedure. This observation motivates the following research question: Given the LSO optimization procedure, how much does the choice of the objective function influence the results and in what way? We address this question empirically in a broad graph clustering context, that is, when graphs are either given as such or are k-nearest-neighbor graphs generated from a given data set. We consider normalized cut, modularity, and infomap, as well as two new objective functions. We show that all these objectives have a resolution bias, that is, they tend to prefer either small or large clusters. When removing this bias, by forcing the objective to generate a given number of clusters, LSO achieves similar performance across the considered objective functions on benchmark networks with built-in community structure. These results indicate that the resolution bias is the most important difference between objective functions in graph clustering with LSO. Spectral clustering is an alternative to LSO, which has been used to optimize the popular normalized cut and modularity objectives. We show experimentally that LSO often achieves superior performance than spectral clustering on various benchmark, real-life, and k-nearest-neighbor graphs. These results, the flexibility of LSO and its efficiency, provide arguments in favor of this optimization method.


Multinational Companies (MNCs) increasingly play an important role in transferring knowledge worldwide. For MNCs, the topic of knowledge transfer has been studied in different ways. While economists have mainly studied the effects of knowledge transfer on firms' performance, management scholars have rather shed light on the processes of transferring knowledge as well as more strategic aspects for MNCs. The objective of this book is to create bridges between economic sciences and management sciences, by highlighting the contributions and methodologies related to each of these disciplines.


The interaction between financial markets and the macroeconomy can be strongly affected by changes in credit market regulations. In order to take account of these effects we control explicitly for regime shifts in a system of debt equations for Norway using a common, flexible trend. The estimated shape of the trend matches the qualitative development in the regulations, and we argue that it can be viewed as a measure of relative credit availability, or credit conditions, for the period 1975-2008 – a credit conditions index (CCI). This entails years of strict credit market regulations in the 1970s, its gradual deregulation in the 1980s, followed by a full-blown banking crisis in the years around 1990 and the development thereafter up to the advent of the current financial crisis. Our study is inspired by Fernandez-Corugedo and Muellbauer (2006), which introduced the methodology and provided estimates of a CCI for the UK. The trend conditions on a priori knowledge about changes in the Norwegian regulatory system, as documented in Krogh (2010b), and it shows robustness when estimated recursively.


In this study, the transient response of a propagating in-plane crack interacting with half-plane boundaries is investigated in detail. The reflected waves which are generated from traction-free boundaries will interact with the propagating crack and make the problem extremely difficult to analyze. The complete transient solutions are constructed by superimposing fundamental solutions in the Laplace transform domain. The fundamental solutions represent the responses of applying exponentially distributed loadings in the Laplace transform domain on the surface of half-plane or the propagating crack faces. We focus our attention on the determination of the dynamic stress intensity factor. The dynamic stress intensity factors of a propagating crack in a configuration with boundaries and subjected to dynamic loadings are obtained in an explicit closed form. The transient solutions obtained in this study are in agreement with the experimental results from the literature. Some interesting phenomena observed in the published experimental works are also identified and discussed. it is concluded that the reflected waves generated from the boundary parallel to the crack have much stronger influence on the propagating crack than those generated from the boundary perpendicular to the crack. When the reflected waves generated from the boundary parallel to the crack return to the moving crack tip, the stress intensity factor will increase rapidly.


This work shows how to leverage causal inference to understand the behavior of complex learning systems interacting with their environment and predict the consequences of changes to the system. Such predictions allow both humans and algorithms to select the changes that would have improved the system performance. This work is illustrated by experiments on the ad placement system associated with the Bing search engine.


Sharks are increasingly being recognized as important members of coral-reef communities, but their overall conservation status remains uncertain. Nine of the 29 reef-shark species are designated as data deficient in the IUCN Red List, and three-fourths of reef sharks had unknown population trends at the time of their assessment. Fortunately, reef-shark research is on the rise. This new body of research demonstrates reef sharks' high site restriction, fidelity and residency on coral reefs, their broad trophic roles connecting reef communities and their high population genetic structure, all information that should be useful for their management and conservation. Importantly, recent studies on the abundance and population trends of the three classic carcharhinid reef sharks (grey reef shark Carcharhinus amblyrhynchos, blacktip reef shark Carcharhinus melanopterus and whitetip reef shark Triaenodon obesus) may contribute to reassessments identifying them as more vulnerable than currently realized. Because over half of the research effort has focused on only these three reef sharks and the nurse shark Ginglymostoma cirratum in only a few locales, there remain large taxonomic and geographic gaps in reef-shark knowledge. As such, a large portion of reef-shark biodiversity remains uncharacterized despite needs for targeted research identified in their red list assessments. A research agenda for the future should integrate abundance, life history, trophic ecology, genetics, habitat use and movement studies, and expand the breadth of such research to understudied species and localities, in order to better understand the conservation requirements of these species and to motivate effective conservation solutions.


ABSTRACT Aim: SNX-5422 is a pro-drug of SNX-2112, a highly potent, non-geldanamycin analogue, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumour models including models of acquired resistance (AR) in EGFR-mutant lung cancer. To prevent disease flare after stopping EGFR tyrosine kinase inhibitors (TKIs) in patients (pts) with EGFR mutant lung cancer, erlotinib (E) is often continued with subsequent lines of treatment for AR. This phase IB study will determine the maximally tolerated dose (MTD) of SNX-5422 and E for pts with mutated EGFR and RECIST progression on EGFR TKIs. Methods: All pts had EGFR mutant lung cancer, with development of AR (per Jackman, JCO 2010) after treatment with an EGFR TKI. Pts underwent repeat tumour biopsies after development of AR and prior to study entry. Pts received SNX-5422 qod, 3 wks on/1 wk off, and E 150mg daily P.O. in 28-day cycles, with dose escalation using a standard 3 + 3 design. Safety and tolerability were evaluated also to determine the MTD and blood samples were obtained for pharmacokinetics. Results: Since May 2013, 17 pts were enrolled. No dose-limiting toxicities (DLTs) were reported in the first cohort (SNX-5422 50 mg/m2 + E), but DLTs (diarrhoea) were reported by 2 pts in the second cohort (SNX-5422 75 mg/m2 + E). Adverse events possibly related to the combination in ≥ 4 of 17 pts in were diarrhoea, nausea, fatigue, dry eyes, paronychia, and rash, all graded 1 or 2; except for 2 cases of grade 3 diarrhoea. No cardiovascular, renal or hepatic toxicities have been observed. 1 Pt reported mild, reversible nictalopia at the DLT level of SNX-5422 75 mg/m2 + E. Pts received a median of two cycles (range 1-6), and 3 remain on study. No partial responses have been seen in 15 evaluable pts; 1 ongoing pt had an 18% decrease from baseline in target lesions in Cycle 4. Stable disease was the best response in 4 pts at 8 wks, 3 pts at 16 weeks and 1 pt at 24 weeks. Conclusions: SNX-5422 and E is a well-tolerated combination at dose levels up to SNX-5422 50 mg/m2 qod + E 150 mg. The MTD was declared SNX-5422 50 mg/m2 + E. Disclosure: J. Hinson: I am employed by Esanex, Inc who is marketing and developing the drug in this study; E. Orlemons: I am employed by Esanex Inc who is developing the agent studied in this trial. I have financial interests including stock ownership. All other authors have declared no conflicts of interest.