BACKGROUND
Recent technologies enable genetic association studies of common clinical analytes on a genomewide basis in populations numbering thousands of individuals. The first publications using these technologies are already revealing novel biological functions for both genic and nongenic loci, and are promising to transform knowledge about the biological networks underlying disease pathophysiology. These early studies have also led to development of a set of principles for conducting a successful genomewide association study (GWAS).

CONTENT
This review focuses on these principles with emphasis on the use of GWAS for plasma-based analytes to better understand human disease, with examples from cardiovascular biology.

CONCLUSIONS
The correlation of common genetic variation on a genomewide basis with clinical analytes, or any other outcome of interest, promises to reveal how parts of the genome work together in human physiology. Nonetheless, performing a genomewide association study demands an awareness of very specific epidemiologic and analytic principles.


This paper studies the design of enforcement policies to detect and deter harmful shortterm activities committed by groups of injurers. With an ordered-leniency policy, the degree of leniency granted to an injurer who self-reports depends on his or her position in the self-reporting queue. By creating a "race to the courthouse," ordered-leniency policies lead to faster detection and stronger deterrence of illegal activities. The socially-optimal level of deterrence can be obtained at zero cost when the externalities associated with the harmful activities are not too high. Without leniency for self-reporting, the enforcement cost is strictly positive and there is underdeterrence of harmful activities relative to the first-best level. Hence, ordered-leniency policies are welfare improving. Our findings for environments with groups of injurers complement Kaplow and Shavell's (1994) results for single-injurer environments.


This study investigated the relationship between the Revised Competitive State Anxiety Inventory-2 (CSAI-2R, Cox, Martens, & Russell, 2003; Jones & Swain, 1992; Martens, Vealey, & Burton, 1990) subscales and the quality of music performance to compare the anxiety-performance relationship in pianists with that in athletes and to gain insights into the effective coping strategies for music performance anxiety (MPA). Fifty one students (15 women and 36 men) aged 18–26 years (M = 20.6, SD = 2.3) completed the CSAI-2R just prior to their individual piano performances in a concert, followed by the self-evaluation of performance quality. The CSAI-2R demonstrated adequate psychometric properties when applied to MPA. Consistent with the previous findings in sport psychology, correlation analyses and multiple regression analyses showed that self-confidence intensity positively predicted global performance (p < .001). Cognitive anxiety intensity negatively predicted technical accuracy (p < .05), while cognitive anxiety direction positively predicted global performance (p < .05). On the other hand, the correlation between somatic anxiety and performance was non-significant. We conclude that acquiring self-confidence, reducing pre-performance cognitive anxiety, and interpreting the symptoms of cognitive anxiety as being facilitative to the subsequent performance will improve performance quality. Based on the present findings, the effectiveness of mental skills training for athletes and some educational methods in treating MPA is discussed.


This article is written from the perspective of empirical research within the broad field of the neuroscience of music (including evolutionary, behavioural, neuroimaging and neuropsychological approaches), with a central theme of the multisensory experience of rhythm and movement in music and dance. Section 1 explores some historical theories on the evolutionary origins of music that point to the important role of rhythmic synchronisation. Section 2 discusses some of the concepts of beat perception and synchronisation in the scientific literature, with examples of various methodologies that have been used to measure these abilities in the body and in the brain. Section 3 focuses on the development in infancy of the musical capacity to 'feel the beat', which involves the integration of auditory and movement information. Section 4 takes a neuropsychological perspective, giving examples of what can go wrong in cases of abnormal music development, and posing some provocative questions about whether or not we all 'have rhythm'. These different perspectives, taken together, reflect a scientific interest in understanding music, movement and the brain. The goal of the article is to find points where neuroscience and music meet, while recognising certain limitations. The discussion is meant to complement important studies and observations in the fields of musicology, music pedagogy, music performance and music therapy by providing empirical support for some of the work of experts in these fields. Ultimately, musicians and scientists together can illuminate the importance of music and movement for the human mind.


Professional translators are highly multitasking agents whose job requires advanced language skills, advanced information literacy, and great technological and instrumental competence. Today they operate in and for an ever more technologized society, within a complex, competitive system of client and user expectations, tools, and new forms of organization and work conditions. This article explores the main industry-level, technological and social developments that have forced many translators to further resituate their practice as co-constructors of knowledge and co-communicators in today's media landscape. It argues that despite the challenges of powerful automatic implementation and the upsurge of volunteer crowdsourcers, professional translators will continue to adapt to evolving work conditions and emerging phenomena, moving the traditional boundaries of the practice and discipline of translation.


Abstract Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.


This paper reviews the literature on IS project success evaluation and finds that the concept of success as currently used in both academia and practice based on the notion of the "triple constraint" – project scope, budget and schedule. This notion of success, derived from engineering, implicitly separates the project to develop the IT artifact from its implementation in the work system it is intended to serve. Additionally, it leads to relativism and lack of direction for project managers. Following Alter (2003), this paper proposes a new conception of project success based on the performance of the IT enabled work system. This conception is shown to be objective, transparent to non-IT managers and to provide direction to project managers in handling changes to projects.


Abstract The government of Hong Kong has been trying to reform the territory's health care financing system since the early 1990s and is finally on the verge of succeeding. The objective of this paper is to assess the reform efforts and explain the causes of repeated failures and eventual success. It will argue that the government's fortunes changed only after it abandoned the core reform goal and decided to pursue peripheral objectives. It will explain the abandonment with reference to the peculiar political system in Hong Kong that makes it difficult for the government to adopt substantial policy reforms in the face of even moderate opposition. The reason for the government's policy incapacity is the existence of liberalism in a non-democratic setting, which allows the government to neither suppress opposition nor mobilize popular support. This has been illustratively evident in its health care reforms when its proposals to improve the system's fiscal sustainability invariably met an early death because they imposed costs on employers, the population or both. The current proposal has fared better not only because it addresses a simpler peripheral problem but also because it offends almost no one and pleases many among the powerful.


The study was aimed at comparing the expectations of Slovak employers and students in terms of employability skills. Twenty-seven companies which employ university graduates working in the manufacturing and financial sectors, represented by a Managing Director or Human Resources Director and 534 university students in the Bratislava region completed a questionnaire that evaluated the perceived importance of, and satisfaction with, generic employability skills. Employers perceived a lack of appropriate skills as the biggest barrier to employing graduates. With regard to the importance of skills, students considered only three skills to be more important than employers did; experience in the field, leadership and authority, and field knowledge. Compared to students, employers regarded engagement and willingness to take on extra work as the most important. In terms of satisfaction, students were more satisfied than employers in nineteen skills from a total of thirty-two. To reduce the satisfaction gap between graduates and employers, higher education institutions can promote students' selfawareness through career psychological services centers.


Abstract The literature is dominated by a paradigm suggesting that the administration of Ronald Reagan was very poor with respect to the advocacy and promotion of international human rights. The "turnaround thesis" contends that only at the end of the Reagan era, after hardliners had left, were those truly concerned with human rights free to exercise a considerable effect on U.S. foreign policy. The contention of this article is that rigid acceptance of the conventional view of Reagan's human rights policy conceals more than it reveals. From the beginning the Reagan team was responsible for substantial contributions in the field of human rights. This will be demonstrated by concentrating on the role played by Dr. Jeane J. Kirkpatrick, U.S. Ambassador to the United Nations and Member of the Presidential Cabinet (1981-5). Kirkpatrick made many important human rights speeches for the administration and offered the most articulate rationale for Reagan's approach. She has been widely criticized by politicians, scholars and human rights activists. However, this paper will offer evidence that many criticisms are unfounded. In 2003 Dr. Kirkpatrick led the U.S. delegation to the United Nations Human Rights Commission. Her approach to human rights, therefore, deserves special attention. Introduction As this paper is being written, the United Nations is on the verge of inaugurating a Human Rights Council. Its first meeting is tentatively scheduled for June, 19, 2006 in Geneva. Whether it will be an improvement over the outgoing Human Rights Commission remains to be seen. There have been numerous calls for UN reform over the years (Hoge 2006; 2005a; Schlesinger 2005). (1) The Oil-for Food fiasco has tarnished the reputation of the organization (Hoge 2005c). The United Nations' performance in human rights has been especially suspect. Its lack of proper action in the former Yugoslavia and Rwanda is scandalous. History appears to be repeating itself in Darfur, Sudan (Hoge 2005b). (2) The U.S. administration of President George W. Bush continues to push to make democracy a reality in Iraq. American authorities have been widely criticized for allegedly torturing some of those in their custody. Meanwhile, Slobodan Milosevic has died in prison before a verdict on his alleged war crimes could be reached and the trial of Saddam Hussein, full of theatrics, goes on and on. The Middle East remains a powder keg filled with charges and countercharges of human rights transgressions. Incapacitation of former Prime Minister Ariel Sharon combined with the ascendance to power of Hamas greatly clouds the Arab-Israeli picture. When Chinese leader Hu Jintao is greeted on the White House lawn, he is heckled by a spectator regarding treatment of the Falun Gong in China. Throngs of people throughout the world protest the publication of cartoons in Denmark said to be blasphemous to Islam. Italy shelters a former-Muslim-turned-Christian while many in his native Afghanistan say his execution is mandated by their faith. It is clear that human rights concerns dominate our world now and will do so in the future. It is also apparent that the United Nations will continue to be linked to many of the world's most intractable human rights dilemmas. The Charter upon which the United Nations rests makes frequent mention of "human rights" (Henkin 1965, 504). As we approach the 5th anniversary of September 11th and the 61st anniversary of the United Nations, it is entirely fitting to assess the role played by this collective security institution in protecting human rights. Such a review is serious business and will help exhibit the strengths and weaknesses of this universal intergovernmental organization. A word of caution is in order. The United Nations as a whole is an extremely complex organization. Those parts of the UN which deal with human rights per se form an intricate labyrinth. Since its inception the UN system for promoting human rights has grown "like topsy"(Alston 1992, 2). …


Second-position enclitics in Cebuano are syntactically dispensable and truth-conditionally irrelevant; however, they add emotional flavor to utterances. This study investigates second-position enclitics in Cebuano, including their form and how they are used to express stance. The objective of this study is to investigate the form and functions of two groups of second-position enclitics, "aspectual" enclitics, and emphasizer and intensifier enclitics, as well as to examine their distribution in enclitic clusters. Conversational data show that the "aspectual" enclitics convey attitudinal stance: =na can convey emphasis, determination, and desperation, while =pa is used to imply "incompletion" or "lack," leading to annoyance. In addition, I discuss =man, illustrating how it is used for downtoning and for showing politeness. I also tease apart the meanings of four seemingly synonymous high-frequency enclitics that differ in their relative frequency and preferred position in a cluster. As to function, =ka'ayo and =gyud serve to emphasize and intensify, but =ka'ayo has a scope over a predicate, while =gyud has scope over an entire proposition. On the other hand, =lagi and =gud have to be inspected in discourse: =lagi has the additional function of asserting one's stance on the hearers, while =gud has the additional element of disagreement or dissatisfaction. Finally, I propose a relative ordering involving these two groups of enclitics in clusters.


ABSTRACT
Using ground-based data, meteorological observations, and atmospheric environmental monitoring data, a comparative analysis of the microphysical and optical properties, and radiative forcing of aerosols was conducted between three stations in different developed environments during a severe air pollution episode during the Spring Festival over Beijing. During the most polluted period, the daily peak values of the aerosol optical depth were ~1.62, ~1.73, and ~0.74, which were about 2.6, 2.9, and 2.1 times higher than the background levels at the CAMS, Xianghe, and Shangdianzi sites, respectively. The daily peak values of the single scattering albedo were ~0.95, ~0.96, and ~0.87. The volume of fine-mode particles varied from 0.04 to 0.21 µm3 µm–2, 0.06 to 0.17 µm3 µm–2, and 0.01 to 0.10 µm3 µm–2, which were about 0.3 to 5.8, 1.1 to 4.7, and 1.2 to 8.9 times greater than the background values, respectively. The daily absorption aerosol optical depth was ~0.01 to ~0.13 at CAMS, ~0.03 to ~0.14 at Xianghe, and ~0.01 to ~0.09 at Shangdianzi, and the absorption Angstrom exponents reflected a significant increase in organic aerosols over CAMS and Xianghe and in black carbon over Shangdianzi. Aerosol radiative forcing at the bottom of the atmosphere varied from –20 to –130, –40 to –150, and –10 to –110 W m–2 for the whole holiday period, indicating the cooling effect. The potential source contribution function and concentration-weighted trajectory analysis showed that Beijing, the southern parts of Hebei and Shanxi, and the central northern part of Shandong contributed greatly to the pollution.


Introduction and objective since particular hypoxia conditions on high altitudes, cause different responses and consistencies in human body, the objective of this research was to study the effects of climbing to altitudes (elevations) on some selected hematological (Platelet) and physiological (Pulse) factors, and stability of changes after returning from elevations. Materials and Methods: 17 non athlete male cases with the average age of 38.7 years were determinedly selected and their blood samples were collected in three stages: Before starting-48 hours after presence on an altitude of 4400 miter, and 72 hours after coming down, and the physiological indexes were studied. Friedman test at the level of (α≤0.05) and spss software version 15 were used to compare the average changes of the three stages. Findings: The results showed that there is a significant difference between the average changes in the three stages so that the average ranks of puke and plate let in the three stages were (2.06-2.94-1) and (1.88-3-1.12) respectively. Discussion and conclusionDeployment at an altitude of 4400 miter for a period of 48 hours causes an increase of platelet and also increase of heart rate to compensate of the shortage of cardiac output because of hypoxia, low temperature and moisture on the elevations. Through reduction of plasma volume, reduced secretion of antidiurtic hormone, and also activation of erythropoitine hormone, and the changes remain relatively stable up to 72 hours after returning down the elevations altitudes.


This study describes and analyzes the German Sickness Insurance Programme in the years between its enactment in 1883 and its recodification in 1911, as part of Germany's comprehensive social insurance system. It traces the evolution of health policy between 1883 and 1911 and discusses the impact that this landmark policy had on the well-being of the German population. Although the antecedents to modern German health policy may be traced to the sixteenth century, the period between 1800 and 1911 is a watershed period. The purpose of the study is twofold: 1) to provide a detailed description of the German model for countries1 without a national health service or national health insurance programme and 2) to study the changing roles of consumers and providers and the effect these changes have on access to care and cost containment, two issues which face policy makers throughout the world. As a social political analysis, this study explores proximate rather than definitive sources and causes for policy decisions. It attempts to delineate and explicate the issues surrounding the need for and enactment of the German Sickness Insurance Act of 1883: Where did the substantive ideas originate. Were they accepted or challenged. By whom. What is the relationship between policy objectives and policy output. How was quality of life affected. The infrastructure of medical services on which the programme relied at its inception is described as are legislative precedents for the Sickness Insurance Act of 1883. The operational aspects of the sickness insurance programme (for example, eligibility criteria, benefit design and programme financing) at the time of its implementation in 1884 are detailed. The study then focuses on the evolution of the programme (that is, changes in eligibility, benefit design and provider reimbursement) and the political and social forces which caused those changes. The interplay between consumer and provider concerns, as well as the changing level of organized input into the policy making process from these two groups is highlighted. The study concludes with an analysis of the programme's impact on the German citizenry, their access to health care and health insurance and the programme's ability to contain costs while expanding access. The analysis specifically assesses the impact that changing roles of consumers and providers have on achieving the goals of access and cost containment. The preconditions for effective implementation of a similarly structured programme elsewhere, specifically the United States, are noted. The limited intervention of the German government in both the financing or administration of the sickness insurance programme as well as its use of a multiple payer system, enhances its political appeal for American legislators and therefore the likelihood that the model could be replicated in the United States.


The purposes of this study were to investigate sprints and to characterize repeated-sprint sequences (RS) performed by athletes during professional futsal matches. We analyzed 97 players during 5 official matches using the DVideo automatic tracking system. The sprints were analyzed during the first and second halves according to playing position, and RS were categorized according to the number of sprints and the time between them. The results showed an increase (F[1, 2520] = 3.96; P = .046) in the sprint duration from the first (mean = 3.1 ± 1.3) to the second half (mean = 3.2 ± 1.2). However, no differences were found for other variables (distance covered, peak velocity, initial velocity, recovery time between sprints, and sprints performed per minute) or among playing positions. In addition, when considering RS, the results showed that RS comprising two sprints interspersed with a maximum of 15 seconds of recovery were significantly more frequent than other RS. The findings of this study characterizing the sprinting features of futsal players can help coaches to plan physical training and assessments according to the requirements of the sport.


Multiagent path planning is important in a variety of fields, ranging from games to robotics and warehouse management. Although centralized control in the joint action space can provide optimal plans, this often is computationally infeasi- ble. Decoupled planning is much more scalable. Traditional decoupled approaches perform a unit-centric decomposition, replacing a multi-agent search with a series of single-agent searches, one for each mobile unit. We introduce an orthogonal, significantly different approach, following a spatial distribution that partitions a map into high- contention, bottleneck areas and low-contention areas. Lo- cal agents called controllers are in charge with one local area each, routing mobile units in their corresponding area. Dis- tributing the knowledge across the map, each controller can observe only the state of its own area. Adjacent controllers can communicate to negotiate the transfer of mobile units. We evaluate our implemented algorithm, SDP, on real game maps with a mixture of larger areas and narrow, bottleneck gateways. The results demonstrate that spatially distributed planning can have substantial benefits in terms of makespan quality and computation speed.


Screening for cardiac health should involve relevant parameters or indices that are easy and inexpensive to obtain. Various cardiac adaptation mechanisms develop during regular exercise that are affected by many factors, and these are reflected on a surface electrocardiogram. QT dispersion has been considered a surrogate for heterogeneity of repolarization, leading to ventricular arrhythmias. We compared QT parameters between athletes and sedentary subjects. A total of 225 men were assessed, comprising a group of professional soccer players and sedentaries. Each subject underwent supine 12-lead electrocardiographic examinations and exercise testing by ergospirometry. QT parameters were taken at rest and at peak exercise. Peak oxygen consumption was considerably higher in the athletes than in the controls (59.3 +/- 5.6 vs. 44.3 +/- 2.4 ml/kg/min, mean +/- SD, p < 0.001). QT parameters at rest: There were significant differences in heart-rate-corrected rest maximal QT duration (413.9 +/- 50.5 vs. 445.3 +/- 45.7 ms, p < 0.001) and in heart-rate-corrected rest minimum QT duration (380.5 +/- 51.2 vs. 409.5 +/- 46.7 ms, p < 0.001). QT parameters at peak exercise: maximal QT duration at peak exercise (253.9 +/- 20.8 vs. 261.7 +/- 26.2, p = 0.02), QT dispersion at peak exercise (25.2 +/- 9.1 vs. 29.5 +/- 15.8 ms, p = 0.04), heart-rate-corrected QT dispersion at peak exercise (44.6 +/- 16.4 vs. 52.6 +/- 28.3 ms, p = 0.03) differed significantly between professional soccer players and controls. QT dispersion and corrected QT dispersion at peak exercise are lower in athletes than in controls. Athletes and other subjects identified with a long QT interval should be examined at regular intervals.


The Ensemble Streamflow Prediction (ESP) system, developed by the National Weather Service (NWS), uses conceptual hydrologic models and historical data to generate a set, or ensemble, of possible streamflow scenarios conditioned on the initial states of a given basin. Using this approach, simulated historical probabilistic forecasts were generated for 14 forecast points in the Colorado River basin, and the statistical properties of the ensembles were evaluated. The median forecast traces were analyzed using ''traditional'' verification measures; these forecasts represented ''deterministic ESP forecasts.'' The minimum-error and historical traces were examined to evaluate the median forecasts and the forecast system. Distribution-oriented verification measures were used to analyze the probabilistic information contained in the entire forecast ensemble. Using a single-trace prediction, for example, the median, resulted in a loss of valuable uncertainty information about predicted seasonal volumes that is provided by the entire ensemble. The minimum-error and historical traces revealed that there are errors in the data, calibration, and models, which are part of the uncertainty provided by the probabilistic forecasts, but are not considered in the median forecast. The simulated ESP forecasts more accurately predicted future streamflow than climatology forecasts and, on average, provided useful information about the likelihood of future streamflow magnitude with a lead time of up to 7 months. Overall, the forecast provided stronger probability statements and became more reliable at shorter lead times. The distribution-oriented verification approach was shown to be applicable to ESP outlooks and appropriate for extracting detailed performance information, although interpretation of the results is complicated by inadequate sample sizes.


1. A manometric and an improved colorimetric method have been employed to study the effect of insect blood on the reaction between carbon dioxide and water. 2. The absence of carbonic anhydrase from insect blood has been confirmed. 3. Neither Locust nor Gastrophilus larva blood contains any substance which inhibits the hydration of carbon dioxide.


Abstract The idea that criminal punishment carries a message of condemnation is as commonplace as could be. Indeed, many think that condemnation is the mark of punishment, distinguishing it from other sorts of penalties or burdens. But for all that torts and crimes share in common, nearly no one thinks that tort has similar expressive aims. And that is unfortunate, as the truth is that tort is very much an expressive institution, with messages to send that are different, but no less important, than those conveyed by the criminal law. In this essay, I argue that tort liability expresses the judgment that the defendant wronged the plaintiff. And I explain why it is important to have an institution that expresses that judgment. I argue that we need ways of treating wrongs as wrongs, so that we can vindicate the social standing of victims. Along the way, I consider the continuity between tort and revenge, and I suggest a new way of thinking about corrective justice and the role that tort plays in dispensing it. I conclude by sketching an agenda for tort reform that would improve tort's ability to serve its expressive function.


Federal and state energy policies have recently emphasized increased renewable energy development, including large utility-scale solar energy projects in the desert southwest. Many of the prime solar development sites in the region are on public land, which is administered primarily by the United States Bureau of Land Management (BLM). Federal public lands policy has therefore been confronted with a rush of project development proposals seeking federal Rights-of-Way (ROWs) from BLM. State permits and licenses, together with compliance with other federal regulatory requirements (especially under the National Environmental Policy Act and the Endangered Species Act) must be coordinated with the BLM ROW grant process. This Article describes the BLM ROW process; describes and evaluates the BLM review for three utility-scale solar energy projects undergoing fast-track permitting under the American Recovery and Reinvestment Act of 2009 in Nevada, Arizona, and California; and evaluates how the BLM's Draft Programmatic Environmental Impact Statement (PEIS) for solar development in the six-state region of Utah, Colorado, New Mexico, Arizona, Nevada, and California could improve the BLM ROW process in order to reduce conflicts between renewable energy development goals and policy concerns about water, work, wildlife, and wilderness in the desert southwest. The Article concludes with recommendations for improving the collaborative federal public lands planning framework for utility-scale solar energy development in the desert southwest. In particular, we recommend policy changes for the PEIS and all BLM ROW grant reviews that will incorporate the best practices of the fast-tracked projects we have analyzed.


Network coding permits to deploy distributed packet delivery algorithms that locally adapt to the network availability in media streaming applications. However, it may also increase delay and computational complexity if it is not implemented efficiently. We address here the effective placement of a limited number of nodes that implement randomized network coding in overlay networks, so that the goodput is kept high while the delay for decoding stays small in streaming applications. We first estimate the decoding delay at each client, which depends on the innovative rate in the network. This estimation permits to identify the nodes that have to perform coding in order to reduce the decoding delay. We then propose two iterative algorithms for selecting the nodes that should perform network coding. The first algorithm relies on the knowledge of the full network statistics. The second algorithm uses only local network statistics at each node. Simulation results show that large performance gains can be achieved with the selection of only a few network coding nodes. Moreover, the second algorithm performs very closely to the central estimation strategy, which demonstrates that the network coding nodes can be selected efficiently with help of a distributed innovative flow rate estimation solution. Our solution provides large gains in terms of throughput, delay, and video quality in realistic overlay networks when compared to methods that employ traditional streaming strategies as well as random network coding nodes selection algorithms.


On 6 April 2009, at 01:32 GMT, an Mw 6.3 seismic event hit the central Apennines, severely damaging the town of L'Aquila and dozens of neighboring villages and resulting in approximately 300 casualties (Istituto Nazionale di Geofisica e Vulcanologia, http://www.ingv.it; MedNet, http://mednet.rm.ingv.it/procedure/events/QRCMT/090406_013322/qrcmt.html). This earthquake was the strongest in central Italy since the devastating 1915 Fucino event ( Mw 7.0). The INGV national seismic network located the hypocenter 5 km southwest of L'Aquila, 8–9 km deep. Based on this information and on the seismotectonic framework of the region, earthquake geologists traveled to the field to identify possible surface faulting (Emergeo Working Group 2009a, 2009b). The most convincing evidence of primary surface rupture is along the Paganica fault, the geometry of which is consistent with seismological, synthetic aperture radar (SAR) and GPS data. Investigation of other known normal faults of the area, i.e. , the Mt. Pettino, Mt. San Franco, and Mt. Stabiata normal faults suggested that these structures were not activated during the April 6 shock (Emergeo Working Group 2009a, 2009b).

In this report, we first describe the seismotectonic framework of the area, and then we present the field information that supports the occurrence of surficial displacement on the Paganica fault.

The shock of 6 April 2009 occurred in a region that has been struck by past earthquakes (CPTI Working Group 2004; Figure 1) and is in an Apennine sector that contains a complex array of active normal faults ( e.g. , Barchi et al. 2000; Galadini and Galli 2000; Boncio et al. 2004; Roberts and Michetti 2004).

In the central Apennines, active faulting and earthquakes result from the ongoing extensional tectonics. The strongest earthquakes in the CPTI04 seismic catalog (CPTI Working Group 2004) occurred on 9 September 1349 ( Mw 6.5) and 2 February …


Products: ı R&S ® VTC ı R&S ® VTE ı R&S ® BTC For A/V devices such as smartphones, tablet PCs, Blu-ray players, set-top boxes and TV sets, the perceived video quality must satisfy very high standards. A/V devices need to hold their own in three main areas: ı Stability (environmental influences, response to source signal disturbances, etc.) ı Performance (switching times, delays) ı Compliance with standards (input and output formats) Any deviations from the expected video and audio output can be automatically and precisely detected with R&S A/V distortion analysis on all common analog and digital interfaces such as HDMI™ and MHL™.


A fad is something that is popular for a time, then unpopular. For example, in the 1960s taili¬ ns on cars were popular, in the 1970s they were not. I study a model in which fads are driven through the channel of imperfect information. Some players have better information about past actions of other players, and all players have preferences for choosing the same actions as well-informed players. In equilibrium, better informed (high-type) players initially pool on a single action choice. Over time, the low-type players learn which action the high-type players are pooling on, and start to mimic them. Once a tipping point is reached, the high-type players switch to a dfferent action, and the process repeats. I explicitly compute equilibria for a specii¬ c parameterization of the model. Low-type players display instrumental preferences for conformity, choosing actions which appear more popular, while high-type players sometimes coordinate on actions which appear unpopular. Improving the quality of information to low-type players does not improve their payoffs, but increases the rate at which high-type players switch between actions.


Learning time-series models is useful for many applications, such as simulation and forecasting. In this study, we consider the problem of actively learning time-series models while taking given safety constraints into account. For time-series modeling we employ a Gaussian process with a nonlinear exogenous input structure. The proposed approach generates data appropriate for time series model learning, i.e. input and output trajectories, by dynamically exploring the input space. The approach parametrizes the input trajectory as consecutive trajectory sections, which are determined stepwise given safety requirements and past observations. We analyze the proposed algorithm and evaluate it empirically on a technical application. The results show the effectiveness of our approach in a realistic technical use case.


The eTalks are a new digital multimedia editing plaform developed at the University of Lausanne: their application is implemented via an easy-to-use editor interface, designed for the use of researchers themselves, to create and edit original eTalks. This permits the linking together of images, sounds and textual materials with hyperlinks, enriching it with relevant information. The final release of eTalks allows complete 'citability' of its contents: each and every portion of the researchers' talks can be precisely referred to and thus cited with a specific identifier, just like any traditional, paper-based scientific publication but with all the potential for plural literacies. It is openly accessible and the code is open source, including guidelines to install the eTalks. It contributes to the development of multiliteracies in the digital academic production of knowledge.


OBJECTIVE
To improve fracture treatment, in vitro experiments were performed to study the influence of a full limb cast and a walking cast on the loading regimen of bones in the distal portion of the equine forelimb.

ANIMALS
6 forelimbs of 6 Shetland ponies.

PROCEDURE
Loading of the third metacarpal bone was considered a representative measure for distal limb loading. Electrical resistance rosette strain gauges were attached to the dorsal, palmar, medial, and lateral surfaces of the midshaft of this bone in 6 forelimbs of 6 Shetland ponies. The limbs were tested in a pneumatic loading device to a maximal load of 1,500 N.

RESULTS
Both casts decreased the amount of compressive forces acting on the metacarpal bone. Application of a full limb cast resulted in a variable and eccentric decrease, remaining strains ranging from 84 to 7% of the baseline value. A walking cast was superior in that it gave a centric and more uniform reduction of compressive loading to < 11% of the baseline value. Moreover, a walking cast neutralized the bending and torsion components of the loading.

CONCLUSION
This study confirmed the clinical experience that a walking cast creates more reliable and favorable conditions for healing of fractures than does a full limb cast.


Stochastic modelling and simulations play a major role in Systems Biology because, at molecular level, biological systems exhibit noise coming both from within the cell (intrinsic) and from the environment (extrinsic). Stochastic modelling takes into account the effects of noise over the system dynamics, that can strongly affect the behavior of the system in conditions of relatively low amounts of molecular species. Stochastic simulations provide an effective way to describe the system dynamics, and can be applied on systems where specified chemical species are processed by a set of biochemical reactions, each one characterized by a stochastic constant. In the context of stochastic modelling, Parameter Sweep Applications (PSAs) can be a useful way to explore the huge spaces generated by the combinations of variables and parameters values in order to test their effects on systems dynamics. PSAs are common in the scientific community and are structured as sets of instances, each one characterized by a distinct parametrisation. A PSA that aims to sample such large spaces must involve a large number of instances and hence the problem becomes very time consuming. However, the independence of each instance of a particular PSA makes the distributed computing paradigm a very useful solution for large scale PSAs. In this work we present a grid based version of a multi-volume stochastic simulator, tau-DPP, implemented on the EGEE project platform. The aim of the proposed work is to exploit this platform for testing the reliability of PSAs over the grid, pointing out critical factors, bottlenecks and scalability by providing data about our experience in this kind of biological modelling and simulations. As a case study, we present a number of PSAs for a stochastic model of bacterial chemotaxis composed of 59 reactions and 31 chemical species.


This study explored beliefs and actual practices of
young women on utilization of Prevention of Mother to Child Transmission
(PMTCT) of HIV services in Balaka district of Southern Malawi. The study design
wascross sectional which utilized qualitative data collection and analysis
methods. In-depth interviews were conducted on 12 young mothers of 15 to 24 years old.
The respondents were drawn from 6 health centres in the district during their
visits to either the under-five clinic, HIV and AIDS support groups or HIV
follow up clinics. Data were analyzed using thematic analysis approach. Overall the respondents had positive beliefs
on utilization of PMTCT services. They believed that adherence to PMTCT
guidelines such as condom use, taking of Nevirapine (NVP) and exclusive
breastfeeding protected the baby from contracting the virus. Nevertheless, all
respondents believed that HIV testing was mandatory and that early weaning
caused malnutrition and death of babies. Actual practice was very low. Very few
young mothers breastfed exclusively, weaned their babies abruptly and took NVP
as recommended. Not all positive beliefs translated into positive behavior.
Lack of male support, inability of the midwives to provide comprehensive care
to HIV infected mothers and their infants, and fear of stigma and
discrimination were other factors that hindered utilization of PMTCT services.
Culture was also a major barrier because traditionally babies are expected to
be breastfed and supplements are fed to babies too. Therefore, there is a need
to mobilize communities on PMTCT
of HIV. Education programmes in HIV should emphasize
behavior change interventions and should focus on both men and women and
significant others. There is also need to intensify monitoring and evaluation
of health workers' activities to ensure that beliefs translate into positive
behavior.


Adobe Dreamweaver CS4 is more than just the worlds most popular and powerful Web design tool: As part of Creative Suite 4 (which includes Photoshop CS4 and Flash CS4), its a key component of an overall Web design workflow that encourages users to rely on all of their applications to seamlessly create graphically rich content for the Web and motion graphics. This information- and image-packed guide lets users get right down to work by providing exact steps for the Dreamweaver CS4 features theyre most likely to need and use, including new features like CSS-based page layout with Absolute Placement objects, Spry datasets for pages built with live data, Spry validation forms for collecting user input, and Spry effects. The book showcases each in a stand-alone tip, complete with a relevant hint or two and helpful screenshot. This is how readers can learn just what they need to know, exploring the program at their own pace to learn just the features and tools they need.


In this article, the concepts and background of regional climate modeling of the future Baltic Sea are summarized and state-of-the-art projections, climate change impact studies, and challenges are discussed. The focus is on projected oceanographic changes in future climate. However, as these changes may have a significant impact on biogeochemical cycling, nutrient load scenario simulations in future climates are briefly discussed as well. The Baltic Sea is special compared to other coastal seas as it is a tideless, semi-enclosed sea with large freshwater and nutrient supply from a partly heavily populated catchment area and a long response time of about 30 years, and as it is, in the early 21st century, warming faster than any other coastal sea in the world. Hence, policymakers request the development of nutrient load abatement strategies in future climate. For this purpose, large ensembles of coupled climate–environmental scenario simulations based upon high-resolution circulation models were developed to estimate changes in water temperature, salinity, sea-ice cover, sea level, oxygen, nutrient, and phytoplankton concentrations, and water transparency, together with uncertainty ranges. Uncertainties in scenario simulations of the Baltic Sea are considerable. Sources of uncertainties are global and regional climate model biases, natural variability, and unknown greenhouse gas emission and nutrient load scenarios. Unknown early 21st-century and future bioavailable nutrient loads from land and atmosphere and the experimental setup of the dynamical downscaling technique are perhaps the largest sources of uncertainties for marine biogeochemistry projections. The high uncertainties might potentially be reducible through investments in new multi-model ensemble simulations that are built on better experimental setups, improved models, and more plausible nutrient loads. The development of community models for the Baltic Sea region with improved performance and common coordinated experiments of scenario simulations is recommended.


The Supreme Court's recent rulings in Arizona v. United States (2012) and Chamber of Commerce v. Whiting (2011) mark a watershed in immigration law and doctrine. Because the Supreme Court held that state and local indirect enforcement measures are no longer permissible, some scholars have argued that this signals the end of state and local engagement in immigration regulation. I believe, to the contrary, that Arizona and Whiting portend a new direction for immigration federalism, with increased emphasis on states' and localities' opportunities to promulgate immigrant-inclusionary measures. This "new immigration federalism" encompasses dynamic and interactive multi-governmental rulemaking pertaining to immigrants and immigration, including rulemaking intended to foster immigrant inclusion. By analyzing recent initiatives for immigration law reform, including Senate Bill 744, the "Border Security, Economic Opportunity, and Immigration Modernization Act," the Obama Administration's Deferred Action for Childhood Arrivals Program, the "Illegal Immigrant Relief Act" lawsuits in Pennsylvania and Texas, the non-cooperation ("sanctuary") ordinances passed in California and Illinois, numerous state "DREAM Act" initiatives for immigration youth, current legal challenges to immigration enforcement statutes in Alabama, Arizona, Utah, Indiana, Georgia, and South Carolina, and numerous immigrant-inclusionary measures enacted by state legislatures since the Court's Arizona opinion, this Article proposes that such developments are best understood within the coherent framework of the new immigration federalism. This new immigration federalism, grounded in immigrant-inclusionary rulemaking, has the potential to inform, complement, and occasionally contradict federal efforts at comprehensive immigration reform.


This is a summary of the 2011 European School Survey Project on Alcohol and Other Drugs (ESPAD) which aims to collect comparable data on substance use among 15?16 year-old European students in order to monitor trends within as well as between countries. This summary presents key results from the 2011 survey as well as findings regarding the long-term trends. An initial section gives a short overview of the methodology.


Communication centers offer speakers an opportunity to engage in a tutoring experience (consultation) where students work with a trained consultant who can help brainstorm, organize, and refine their oral presentation. Consultants working in communication centers are often faced with the issue of how to engage their speaker during the consultation. In this article, the author discusses how communication center consultants can employ journalistic techniques to engage students in the critical thinking process. Four techniques employed by journalists during an interview that communication center consultants can implement into their consultations are: begin with the easy questions, maintain self-control, listen and listen well, and take nothing at face value. Consultants providing students with feedback on brainstorming and organization can best implement these techniques and offer a way to critically think about a speech and allow the speaker to take on an active role in the learning environment.


Rights to service billions of dollars of mortgages change hands each year. While the reasons for purchases vary, the most common ones include improvements to cash flow or profitability; accounting concerns; and the urge to improve the efficiency of the entire servicing portfolio by bulking up. These servicing transfers can produce the intended results - or significant and costly difficulties. The key to success is planning well in advance of the transfer date; in fact, the effort should begin when the decision is made to pursue this means of portfolio enhancement. Bulk purchase basics. Most banks and mortgage banking firms use three methods to build portfolios. The basic is retail production, followed by wholesale purchases from correspondents. The third method is bulk acquisition of servicing rights or loans held by others. The first two methods produce whole loans with the accompanying overhead. The institution also faces risks in selling the loans into the secondary market. On the other hand, bulk acquisitions of servicing present neither of these risks, and the strategy may be started or stopped easily and quickly. Yet this relative ease frequently creates problems. For example, at many financial institutions, the servicing manager is not consulted before the acquisition. Stories frequently circulate of CEOs or other officers who call the servicing manager with the news that $1 billion of, say, Federal National Mortgage Association, servicing has been purchased and will arrive in two weeks. The fact that the servicing department may not be adequately staffed to handle the acquisition in that time frame was not considered. Nor was it considered that the company is not a Farmie Mae-approved servicer and, if it were, that 45 days' lead time would be required. Ideally, the servicing manager should be a member of the acquisition committee and an integral part of the decision and planning process. Scoping things out. Most successful firms consider prior review of a specific portfolio the most crucial period. What are the characteristics of the portfolio? Is it too large to absorb comfortably? Can adequate service be provided to new customers without neglecting the existing portfolio? Remember that years of customer-related problems led to the inclusion of transfer provisions in the Cranston-Gonzalez National Affordable Housing Act of 1990. (ABA BJ, Feb., p. 28.) Is the timing appropriate? Year-end is a busy period for all firms and may be a poor point to make an acquisition. There are other bad times to make a big purchase, among them, tax season, when summer vacations have already been scheduled, and when massive escrow analysis has just been done. (When an institution performs a portfolio-wide analysis and notifies borrowers of necessary changes, switchboards light up and everyone gets very busy.) There are other potential problems to consider: What types of loans are included in the portfolio? Are they compatible with the existing portfolio? How old are the loans? Location is another consideration. Say the loans are in states other than those in which you currently operate. It may be necessary to seek legal opinions as to specific state requirements and possible licensing requirements. Each of these items takes time to resolve. Data processing requirements demand scrutiny. Almost every portfolio offering states that a "tape-to-tape" conversion is possible. "Possible" means many things. Virtually all servicing software systems can provide a direct input to the purchaser's system, but the costs of producing it may not make this approach feasible. This is particularly true in the acquisition of a small portfolio. A 5,000-loan portfolio can usually be loaded from one system to another for only a bit more than a 1,000-loan portfolio. For the reasons of compatibility, cost, and lead time, you should always include your systems people in the initial portfolio considerations. …


The requirements are given for absolute calibration of a spectroradiometer by means of an extended standard source. In some cases the extended source may be used without auxiliary optics, but in many cases a concave mirror is necessary or desirable. For such a mirror, a relation between incident and reflected steradiancy is derived. Brandenberg's focusing relations for a concave spherical mirror are extended and applied to four practical cases, and it is shown that no loss in accuracy of calibration will result from the use of such mirrors provided that the source and the mirror are large enough. Experimental verification is given.


Metal intoxication, thus is an important concern in the world today owing to high industrial and chemical exposure to humans. These metal toxicities have been extensively studies with underlying mechanisms revealed up to molecular levels. However, much emphasis and focus on managing these metal-induced toxic manifestations is the need of the hour. Chelation therapy has long been surrounded with debates and challenges for unanimous acceptance despite being the only option. Conventionally known chelating agents although show therapeutic efficacy, yet more specific and safer profile drugs are needed. Newer therapeutic strategies like combination therapy (administration of two chelating agents) or co-administration of chelating agent with antioxidants and/or essential metals needs to be clinically refined and implemented.


Manichaeism was a successful missionary religion during the time of the Sasanians with a well-constructed system of doctrines and an overall church organization. For more than thirty years Mani's religion spread peacefully not only across Iran and its neighboring countries but also gained ground in Egypt, Roman Empire and parts of India.
It was towards the end of Shapur's reign, about 270 AD that the resistance of the magi against the rapidly progressing religion began to form. Mani died in prison during the reign of King Wahram I, who had come to disdain and fear the new religion. The fierce persecution of Mani's disciples confined his religion to a small part of the Iranian Empire. Manichaeism disappeared in Europe in the 6th century, in Byzantine Empire by the 9th century, and in the Islamic World in 11th century. Only in China did it survive until 16th century.
By stressing the social worth of the merchant and moneyed classes and denigrating manual labor, and debasing marriage and procreation, Manichaeism was deprived of an extended base of social support. Furthermore, despite Mani's claims that his religion provided answers to man's basic questions about nature, creation and the origins of good and evil, his teachings were essentially rooted in mythology. Indeed many of his ideas were widely ridiculed by a number of Christian theologians and Muslim philosophers.


Financial contagion and systemic risk measures are commonly derived from conditional quantiles by using imposed model assumptions such as a linear parametrization. In this paper, we provide model free measures for contagion and systemic risk which are independent of the specification of conditional quantiles and simple to interpret. The proposed systemic risk measure relies on the contagion measure, whose tail behavior is theoretically studied. To emphasize contagion from extreme events, conditional quantiles are specified via hierarchical Archimedean copula. The parameters and structure of this copula are simultaneously estimated by imposing a non-concave penalty on the structure. Asymptotic properties of this sparse estimator are derived and small sample properties illustrated using simulations. We apply the proposed framework to investigate the interconnectedness between American, European and Australasian stock market indices, providing new and interesting insights into the relationship between systemic risk and contagion. In particular, our findings suggest that the systemic risk contribution from contagion in tail areas is typically lower during times of financial turmoil, while it can be significantly higher during periods of low volatility. JEL classification: C40, C46, C51, G1, G2


We use 3D seismic data to image a series of enigmatic, SW-dipping reflection packets within pre-Mesozoic crystalline basement offshore western Norway. Based on their low-angle dip and complex reflection wave-train our preferred interpretation is that the reflection packets are the seismic expression of mylonitic zones generated by nappe emplacement during the Caledonian orogeny. Late Jurassic faults truncate and offset these reflection packets by several hundred metres, suggesting that these faults did not exploit pre-existing basement weaknesses. Our observations suggest that older basement fabrics may not always play a significant role in determining the geometry of later fault systems. Supplementary materials: Details of the time-depth relationships from wells that have been used to depth-convert interpretations (S1), a supplementary figure showing an uninterpreted version of the seismic profile presented in Fig. 2 (S2) and a throw v. distance plot for fault F1 at the structural levels of the basement reflection and intra-basement reflection 1 are available at www.geolsoc.org.uk/SUP18683.


Introduction: We aim to determine to what degree whole-slide images (WSI) can be compressed without impacting the ability of the pathologist to distinguish benign from malignant tissues. An underlying goal is to demonstrate the utility of a visual discrimination model (VDM) for predicting observer performance. Materials and Methods: A total of 100 regions of interest (ROIs) from a breast biopsy whole-slide images at five levels of JPEG 2000 compression (8:1, 16:1, 32:1, 64:1, and 128:1) plus the uncompressed version were shown to six pathologists to determine benign versus malignant status. Results: There was a significant decrease in performance as a function of compression ratio (F = 14.58, P < 0.0001). The visibility of compression artifacts in the test images was predicted using a VDM. Just-noticeable difference (JND) metrics were computed for each image, including the mean, median, ≥90th percentiles, and maximum values. For comparison, PSNR (peak signal-to-noise ratio) and Structural Similarity (SSIM) were also computed. Image distortion metrics were computed as a function of compression ratio and averaged across test images. All of the JND metrics were found to be highly correlated and differed primarily in magnitude. Both PSNR and SSIM decreased with bit rate, correctly reflecting a loss of image fidelity with increasing compression. Observer performance as measured by the Receiver Operating Characteristic area under the curve (ROC Az) was nearly constant up to a compression ratio of 32:1, then decreased significantly for 64:1 and 128:1 compression levels. The initial decline in Az occurred around a mean JND of 3, Minkowski JND of 4, and 99th percentile JND of 6.5. Conclusion: Whole-slide images may be compressible to relatively high levels before impacting WSI interpretation performance. The VDM metrics correlated well with artifact conspicuity and human performance.


America's economic future is uncertain. Mired in a long crippling economic slump and hamstrung by bitter partisan debate over the growing debt and the role of government, the nation faces substantial challenges, exacerbated by a dearth of vision and common sense among its leaders. Prominent Stanford economist John B. Taylor brings his steady voice of reason to the discussion with a natural solution: start with the country's founding principles of economic and political freedom-limited government, rule of law, strong incentives, reliance on markets, a predictable policy framework-and reconstruct its economic foundation from these proven principles. Channeling his high-level experience as both a policymaker and researcher, Taylor then zeroes in on current policy issues-the budget, monetary policy, government regulation, tax reform-and lays out in simple terms bold strategies designed to place the country on sound footing in each of these areas.


We use a global metapopulation transmission model to study the establishment of sustained and undetected community transmission of the COVID-19 epidemic in the United States. The model is calibrated on international case importations from mainland China and takes into account travel restrictions to and from international destinations. We estimate widespread community transmission of SARS-CoV-2 in February, 2020. Modeling results indicate international travel as the key driver of the introduction of SARS-CoV-2 in the West and East Coast metropolitan areas that could have been seeded as early as late-December, 2019. For most of the continental states the largest contribution of imported infections arrived through domestic travel flows.


This article presents the findings of an intersectional study on migrant women on German television. Besides content and textual analyses, we conducted focus groups with audiences and interviews with migrant media workers. As the representation of Others was explored through the nodes of production, consumption, and identity, a complicated intersectional practice emerged. We found the televised representations of migrant women to be dominated by (often veiled) women as signifiers of non-integration but also by instances when gendered ethnicity was used as a marketable attribute. The audiences and producers employed various distancing strategies: they criticized specific programs for blatant stereotyping as much as didactic counter-stereotyping while downplaying systemic shortfalls of the coverage. These distancing strategies were intensified by the acceptance of individualized ideologies of success and commodified logics of media production. Ultimately, class appeared as the central demarcating category. On German television a problematic class distinction was articulated through ethnic and gender difference. Female migrants were often "othered" as lower-class. This class discourse absolved middle-class viewers and media workers from engaging in the systemic struggles over female/migrant identities, thus undermining the potential for gender and migrant solidarity and for the dynamic creation of cultural citizenship as a mode of belonging.


Parallel workstations, each comprising 10-100 processors, promise cost-effective general-purpose multiprocessing. This paper explores the coupling of such small- to medium-scale shared memory multiprocessors through software over a local area network to synthesize larger shared memory systems. We call these systems Distributed Scalable Shared-memory Multiprocessors (DSSMPs).This paper introduces the design of a shared memory system that uses multiple granularities of sharing, and presents an implementation on the Alewife multiprocessor, called MGS. Multigrain shared memory enables the collaboration of hardware and software shared memory, and is effective at exploiting a form of locality called multigrain locality. The system provides efficient support for fine-grain cache-line sharing, and resorts to coarse-grain page-level sharing only when locality is violated. A framework for characterizing application performance on DSSMPs is also introduced.Using MGS, an in-depth study of several shared memory applications is conducted to understand the behavior of DSSMPs. We find that unmodified shared memory applications can exploit multigrain sharing. Keeping the number of processors fixed, applications execute up to 85% faster when each DSSMP node is a multiprocessor as opposed to a uniprocessor. We also show that tightly-coupled multiprocessors hold a significant performance advantage over DSSMPs on unmodified applications. However, a best-effort implementation of a kernel from one of the applications allows a DSSMP to almost match the performance of a tightly-coupled multiprocessor.


Abstract Smooth solid DT layers inside a spherical shell are needed in order to achieve ignition on the Laser MegaJoule (LMJ) facility. This paper presents a few novel techniques developed in our lab to achieve the required temperature and surface roughness conditions. Results are presented that confirm our hypotheses and lead us to be confident that we may achieve the requirements for the cryogenic LMJ ignition target.


Aim To determine predictive risk factors for violent offending in patients with paranoid schizophrenia in Croatia. Method The cross-sectional study including male in-patients with paranoid schizophrenia with (N = 104) and without (N = 102) history of physical violence and violent offending was conducted simultaneously in several hospitals in Croatia during one-year period (2010-2011). Data on their sociodemographic characteristics, duration of untreated illness phase (DUP), alcohol abuse, suicidal behavior, personality features, and insight into illness were collected and compared between the groups. Binary logistic regression model was used to determine the predictors of violent offending. Results Predictors of violent offending were older age, DUP before first contact with psychiatric services, and alcohol abuse. Regression model showed that the strongest positive predictive factor was harmful alcohol use, as determined by AUDIT test (odds ratio 37.01; 95% confidence interval 5.20-263.24). Psychopathy, emotional stability, and conscientiousness were significant positive predictive factors, while extroversion, pleasantness, and intellect were significant negative predictive factors for violent offending. Conclusion This study found an association between alcohol abuse and the risk for violent offending in paranoid schizophrenia. We hope that this finding will help improve public and mental health prevention strategies in this vulnerable patient group.


Background: Measuring workplace bullying is a challenge as different workforces have different issues. Objectives: The aim of this study was to evaluate the construct validity and reliability of a Workplace Bullying Inventory (WBI) that was originally derived and validated in a nursing workforce in a broader sample of the Australian public sector workforce. Method: A two-stage procedure was employed with a large sample of volunteer public sector workforce union members (n=1,508), randomly split in two halves. The first sample (n=754) was analysed using exploratory factor analysis (EFA) and the second sample (n=754) through confirmatory factor analysis (CFA) using MPlus. The WBI consisted of 20 items related to bullying behaviours; 17 of which we had previously validated for use in an Australian nursing workforce. An additional 3 items were included from other workforce bullying scales in order to enhance the generalizability of the scale to a wider workforce. Results: The final model, identified in sample 1 and validated in sample 2 (CFA), best represented workplace bullying as three reliable first-order factors, together loading 13 items; Social Intimidation with 6 items (α = 0.88), Personal Attack with 4 (α = 0.84) and Attack through Work Tasks with 3 items (α= 0.85). Discussion: The modelling demonstrates that workplace bullying is a complex construct, consisting of multiple factors. The original measure derived from the nursing workforce demonstrates broad applicability in different public sector workforce contexts. Differences in the factor structure of the WB construct in this study when compared to the earlier nursing study suggest subtle differences may exist in the nature of bullying across workgroup settings. Future work in theory development should investigate further the complexities of the construct in order to learn how to manage and ultimately prevent WB behaviours.


As the life sciences have become more data intensive, the pressure to incorporate the requisite training into life-science education and training programs has increased. To facilitate curriculum development, various sets of (bio)informatics competencies have been articulated; however, these have proved difficult to implement in practice. Addressing this issue, we have created a curriculum-design and -evaluation tool to support the development of specific Knowledge, Skills and Abilities (KSAs) that reflect the scientific method and promote both bioinformatics practice and the achievement of competencies. Twelve KSAs were extracted via formal analysis, and stages along a developmental trajectory, from uninitiated student to independent practitioner, were identified. Demonstration of each KSA by a performer at each stage was initially described (Performance Level Descriptors, PLDs), evaluated, and revised at an international workshop. This work was subsequently extended and further refined to yield the Mastery Rubric for Bioinformatics (MR-Bi). The MR-Bi was validated by demonstrating alignment between the KSAs and competencies, and its consistency with principles of adult learning. The MR-Bi tool provides a formal framework to support curriculum building, training, and self-directed learning. It prioritizes the development of independence and scientific reasoning, and is structured to allow individuals (regardless of career stage, disciplinary background, or skill level) to locate themselves within the framework. The KSAs and their PLDs promote scientific problem formulation and problem solving, lending the MR-Bi durability and flexibility. With its explicit developmental trajectory, the tool can be used by developing or practicing scientists to direct their (and their team's) acquisition of new, or to deepen existing, bioinformatics KSAs. The MR-Bi can thereby contribute to the cultivation of a next generation of bioinformaticians who are able to design reproducible and rigorous research, and to critically analyze results from their own, and others', work.


Noting that some Rab GTPases (guanosine triphosphatases) have been implicated in embryogenesis, Lee et al. injected mRNA encoding Rab proteins into developing Xenopus embryos and found that the protein encoded by one of them inhibited gastrulation. This protein, XRab40, contained not only a GTPase domain but also a SOCS (suppressors of cytokine signaling) box domain. SOCS-box proteins associate with Elongin B and Elongin C as part of Cullin-based ubiquitin ligase complexes, and a combination of mass spectrometry analysis, yeast two-hybrid assays, and pull-down assays revealed that XRab40 interacted with the Xenopus homologs of Elongins B and C and Cullin5, and with the XRap2 GTPase. The SOCs box was required for XRab40 binding to XElonginB, XElonginC, and XCul5, whereas the GTPase domain was required for interaction with XRap2. XRab40 localized to the Golgi, and this localization depended on the SOCs box. Although wild-type XRab40 rescued gastrulation defects produced by antisense morpholino oligonucleotides directed against XRab40 (XRab40 Mo), mutants that did not localize to the Golgi failed to do so. Moreover, morpholinos directed against XCul5 (XCul5 Mo), which inhibited localization of XRab40 to the Golgi, elicited a phenotype similar to that of XRab40 Mo, as did a Cul5 dominant-negative mutant. XRab40 knockdown or mislocalization led to XRap2 mislocalization and a decrease in XRap2 ubiquitination (but not its stability). XRap2 bound to XMINK (Misshapen/Nck-interacting kinase) and morpholinos directed against XMINK also elicited gastrulation defects. Analyses of the ability to rescue morpholino-induced phenotypes indicated that XMINK acted downstream of XRab40 and XRap2. XMINK bound to Dishevelled (Dsh), translocation of which to the plasma membrane has been implicated in noncanonical Wnt signaling. Morpholinos directed against XRab40, XCul5, and XMINK inhibited Dsh localization to the plasma membrane when the Wnt pathway was activated. Thus, the authors conclude that XRab40 participates in a Cullin-based ubiquitin ligase complex, which regulates noncanonical Wnt signaling by way of XRap2 and XMINK and plays a critical role in Xenopus gastrulation. R. H. K. Lee, H. Iioka, M. Ohashi, S.-i. Iemura, T. Natsume, N. Kinoshita, XRab40 and XCullin5 form a ubiquitin ligase complex essential for the noncanonical Wnt pathway. EMBO J. 26, 3592-3606 (2007). [PubMed]


Pre-surgical BRCA1/2 genetic testing provides valuable risk information to guide a newly-diagnosed breast cancer patient's decision about whether to have a contralateral prophylactic mastectomy (CPM) to reduce her future risk of cancer in her unaffected breast. Although BRCA1/2 mutation noncarriers face a much lower objective ten-year risk of developing contralateral disease (approximately 3–10%) as compared to the risk of BRCA1/2 mutation carriers (27–37%), some noncarriers still choose to undergo a CPM. The psychosocial factors that motivate this decision are not well understood and warrant investigation. Thus, as part of a prospective study of pre-surgical BRCA1/2 testing, we examined the frequency and psychosocial correlates of the decision to undergo a CPM among newly-diagnosed breast cancer patients who were identified as BRCA1/2 mutation noncarriers. Self-report questionnaire data from 90 BRCA1/2 noncarriers (median age = 43 years, range = 29–59) were analyzed. A sizeable minority of the BRCA1/2 noncarriers (24.4%) chose to undergo a CPM after learning their mutation status (compared to 88% of the 8 BRCA1/2 carriers in the sample). Both bivariate and multivariable analyses indicated that perceiving that one's physician had recommended CPM (OR = 11.17, P = 0.007), perceiving greater risk for contralateral breast cancer (OR = 6.46, P = 0.02), and perceiving greater pros of CPM (OR = 1.37, P = 0.004) were all significantly associated with noncarriers' decision to undergo CPM. However, factors including age, Ashkenazi Jewish ethnicity, breast cancer-related distress, perceived cons of CPM, and decisional conflict regarding CPM were not related to the CPM decision (all ps > 0.05). Results demonstrate that although noncarriers' decision making regarding CPM was unrelated to sociodemographic and emotional factors, their cognitive perceptions of contralateral disease risk, surgical benefits, and physician recommendations were particularly important. Future studies should examine the content of patient-physician communication regarding CPM and hereditary risk in greater detail, and explore how these conversations shape and interact with women's past experiences, emotions, and beliefs to influence their cancer prevention decisions.


Coccidioidomycosis is a highly variable disease. Initial respiratory tract infection can lead to self-limited pneumonia, pulmonary complications, and extrapulmonary disease. The early infection requires no therapy, except in immunosuppressed patients and other selected patients. Treatment for pulmonary complications may include surgery for cavities or pyopneumothorax (resulting from rupture of a cavity) and antifungal therapy for chronic pneumonia. The majority of extrapulmonary disease occurs in the skin, bones and joints, or meninges and is an indication for treatment with antifungal agents and sometimes adjunctive surgery. Meningitis is a particularly serious consequence of dissemination and currently is best treated with intrathecal instillation of antifungal agents. Antifungal agents useful in the treatment of coccidioidomycosis are amphotericin B, which is administered intravenously and is relatively toxic, and ketoconazole, which is administered orally and whose toxicities are less serious and reversible. Because studies to compare the efficacy of these two drugs have not been performed, selecting between them for use in individual patients is most rationally based on the pharmacologic differences, which lend themselves to different clinical settings. In future years, new antifungal agents will likely be available, some of which will offer significant advantages over present therapies. Itraconazole is an imidazole related to ketoconazole, which appears to be effective and possibly less toxic than ketoconazole. Fluconazole, another imidazole, has broad antifungal activity, a long serum half-life, and excellent penetration into the cerebrospinal fluid. Thus, the pharmacology of this agent would appear ideal for use in treating coccidioidal meningitis. In addition, other compounds with different modes of action are now under investigation in preclinical studies. It is therefore likely that continued improvements will occur in the coming years in the treatment of this disease.


Data sparsity is one of the main factors that make word sense disambiguation (WSD) difficult. To overcome this problem we need to find effective ways to use resources other than sense labeled data. In this paper I describe a WSD system that uses a statistical language model based on a large unannotated corpus. The model is used to evaluate the likelihood of various substitutes for a word in a given context. These likelihoods are then used to determine the best sense for the word in novel contexts. The resulting system participated in three tasks in the SemEval 2007 workshop. The WSD of prepositions task proved to be challenging for the system, possibly illustrating some of its limitations: e.g. not all words have good substitutes. The system achieved promising results for the English lexical sample and English lexical substitution tasks.


Vitamin D insufficiency is seasonally endemic in populations north of the 40th parallel, and epidemiological data show an association with colorectal cancer risk and prognosis. Molecular mechanisms that underpin the relationship are not well established. Vitamin D status is shown to be associated with age-related silencing of tumour suppressors in colonic stem cells via aberrant DNA methylation, suggesting that insufficiency contributes to transformation. In this text, vitamin D's ability to promote bowel health via modification of DNA methylation patterns has been investigated.
Chronic inflammation drives tumourigenesis, and vitamin D is recognised to promote proper immune function. Data presented here confirm that vitamin D differentiates monocytes to a tissue-resident macrophage phenotype. D-mediated differentiation is associated with hypomethylation of the TNFα promoter and response to LPS. Thus, we suggest that vitamin D attenuates aberrant DNA methylation in colonic stem cells by promoting resolution of systemic inflammation.
Mucosal inflammation mediated by PGE2 promotes aberrant DNA methylation. Pericryptal myofibroblasts interact with colonic stem cells via their secretomes, which are a source of PGE2. Supernatants from primary intestinal myofibroblasts were characterised by LC/MS mass spectroscopy in response to vitamin D. Vitamin D attenuated TNFα-induced transcription of COX2 and PGE2 secretion. PGE2 induced hypermethylation of SOX17 and DKK1 in colonic organoids, and myofibroblast supernatants regulated DNA methyltransferase activity in case-matched organoids. Furthermore, vitamin D ameliorated established aberrant DNA methylation in organoids propagated from inflamed mucosa. Thus, we suggest that vitamin D attenuates mucosal inflammation, and the effects of PGE2 driving aberrant DNA methylation in colonic stem cells.
Vitamin D status predicts colorectal cancer survival. The effects of vitamin D sufficiency on colorectal cancer cell lines was investigated. Vitamin D-treated cells exhibit a modified methylome, reduced transcription of MAP kinases, reduced phosphorylation of ERK1 and 2, and inhibition of proliferation. Thus we suggest that vitamin D sufficiency improves colorectal cancer prognosis via modification of established aberrant DNA methylation. Taken together, data support vitamin D sufficiency promoting bowel health via attenuation of aberrant age-related DNA methylation in colonic stem cells.


We introduce the fluctuating two-ray (FTR) fading model, a new statistical channel model that consists of two fluctuating specular components with random phases plus a diffuse component. The FTR model arises as the natural generalization of the two-wave with diffuse power (TWDP) fading model; this generalization allows its two specular components to exhibit a random amplitude fluctuation. Unlike the TWDP model, all the chief probability functions of the FTR fading model (PDF, CDF, and MGF) are expressed in closed-form, having a functional form similar to other state-of-the-art fading models. We also provide approximate closed-form expressions for the PDF and CDF in terms of a finite number of elementary functions, which allow for a simple evaluation of these statistics to an arbitrary level of precision. We show that the FTR fading model provides a much better fit than Rician fading for recent small-scale fading measurements in 28 GHz outdoor mm-wave channels. Finally, the performance of wireless communication systems over FTR fading is evaluated in terms of the bit error rate and the outage capacity, and the interplay between the FTR fading model parameters and the system performance is discussed. Monte Carlo simulations have been carried out in order to validate the obtained theoretical expressions.


Piecing Together Hydrogenase Microbial hydrogenase enzymes generally use iron to catalyze the reversible formation of hydrogen from protons and electrons. Key to their efficiency is a set of iron-coordinating ligands, including CO and cyanide. Kuchenreuther et al. (p. 472) examined how the HydG maturase enzyme breaks down the amino acid tyrosine to derive these diatomic ligands for assembly of the diiron class of hydrogenases. The first step involves abstraction of an H atom from the phenolic OH substituent of the side chain. Electron paramagnetic resonance spectroscopy revealed a radical intermediate that subsequently results from heterolysis of the bond tethering the side chain to the α-carbon. With the side chain thus jettisoned, the residual dehydroglycine could be transformed into CO and CN−. Electron paramagnetic resonance spectroscopy elucidates a key step in the biosynthesis of hydrogenase active site ligands. The radical S-adenosylmethionine (SAM) enzyme HydG lyses free l-tyrosine to produce CO and CN− for the assembly of the catalytic H cluster of FeFe hydrogenase. We used electron paramagnetic resonance spectroscopy to detect and characterize HydG reaction intermediates generated with a set of 2H, 13C, and 15N nuclear spin-labeled tyrosine substrates. We propose a detailed reaction mechanism in which the radical SAM reaction, initiated at an N-terminal 4Fe-4S cluster, generates a tyrosine radical bound to a C-terminal 4Fe-4S cluster. Heterolytic cleavage of this tyrosine radical at the Cα-Cβ bond forms a transient 4-oxidobenzyl (4OB•) radical and a dehydroglycine bound to the C-terminal 4Fe-4S cluster. Electron and proton transfer to this 4OB• radical forms p-cresol, with the conversion of this dehydroglycine ligand to Fe-bound CO and CN−, a key intermediate in the assembly of the 2Fe subunit of the H cluster.


Let's face it, dealing with customers isn't easy. They aren't always right?or even pleasant?but knowing the right words to use can make all the difference.

Powerful Phrases for Effective Customer Service shares over 700 phrases and scripts that have been proven time and again to defuse even the most difficult interactions. Covering 30 challenging customer behaviors and 20 tough employee-caused situations, this indispensible reference makes it easy for readers to assess the circumstances, find the appropriate response, and confidently deliver satisfaction to every customer. In addition, readers will learn how to incorporate language into their daily routine that communicates welcome, courtesy, rapport, enthusiasm, assurance, regret, empathy, and appreciation. Every chapter includes helpful Do This! sample scenarios that bring the phrases to life as well as Why This Works sections that provide detailed explanations.

Practical and insightful, Powerful Phrases for Effective Customer Service ensures that employees will never again be at a loss for words when dealing with customers.


Extreme responses of a droplet ensemble during an entrainment and mixing process as present at the edge of a cloud are investigated by means of three-dimensional direct numerical simulations in the Euler–Lagrangian framework. We find that the Damköhler number Da, a dimensionless parameter which relates the fluid time scale to the typical evaporation time scale, can capture all aspects of the initial mixing process within the range of parameters accessible in this study. The mixing process is characterized by the limits of strongly homogeneous (Da ≪ 1) and strongly inhomogeneous (Da ≫ 1) regimes. We explore these two extreme regimes and study the response of the droplet size distribution to the corresponding parameter settings through an enhancement and reduction of the response constant K in the droplet growth equation. Thus, Da is varied while Reynolds and Schmidt numbers are held fixed, and initial microphysical properties are held constant. In the homogeneous limit minimal broadening of the size distribution is observed as the new steady state is reached, whereas in the inhomogeneous limit the size distribution develops strong negative skewness, with the appearance of a pronounced exponential tail. The analysis in the Lagrangian framework allows us to relate the pronounced negative tail of the supersaturation distribution to that of the size distribution.


John Rawls' text The Law of Peoples has inspired extensive scholarly debate in the field of international political theory, since its publication in 1999. Responding to the arguments of cosmopolitan theorists and Amartya Sen's recent critique, this new work presents a fresh appraisal of the debate, and argues that Rawls offers a persuasive and prescient moral perspective on issues of global poverty and development. By elaborating one of Rawls' core ideas, 'the duty of assistance', the book offers a unique theoretical response to the ideal of global justice. The duty is presented as a far-reaching principle of justice, one that advocates increasing the state capability of burdened societies, and aims to compel the most powerful states to reform international structures and provide aid, in a constructive and culturally sensitive manner. The aim of assistance is the strengthening of democratic, or 'decent' indigenous institutions and the promotion of the freedom of peoples. On Rawls, Development and Global Justice is an original contribution to current debates on international redistribution, democracy promotion and global poverty.


This Essay describes the evolution of feminist legal scholarship, using six articles published by the California Law Review as exemplars. This short history provides a window on the most important contributions of feminist scholarship to understandings about gender and law. It explores alternative formulations of equality, and the competing assumptions, ideals, and implications of these formulations. It describes frameworks of thought intended to compensate for the limitations of equality doctrine, including critical legal feminism, different voice theory, and nonsubordination theory, and the relationships between these frameworks. Finally, it identifies feminist legal scholarship that has crossed the disciplinary boundaries of law. Among its conclusions, the Essay points out that as feminist scholarship has become more mainstream, its assumptions and methods are less distinct. It observes that even as feminist legal scholarship has generated important, insightful critiques of equality doctrine, it remains committed to the concept of equality, as continually revised and refined. The Essay also highlights the importance of feminist activism and practice in sharpening and refining feminist legal scholarship.


STUDY DESIGN
Prospectively collected, multicenter, nationwide study.

OBJECTIVE
To investigate recent surgical methods and trends, outcomes, and perioperative complications in surgery for thoracic ossification of the ligamentum flavum (T-OLF).

SUMMARY OF BACKGROUND DATA
A prospective multicenter study of surgical complications and risk factors for T-OLF has not been performed, and previous multicenter retrospective studies have lacked details for these items.

METHODS
Surgical methods, pre- and postoperative thoracic myelopathy (Japanese Orthopaedic Association (JOA) score), symptoms, and intraoperative neurophysiological monitoring (IONM) were investigated prospectively in 223 cases. Differences in these factors between fusion and non-fusion procedures for T-OLF were examined. The minimum follow-up period was 2 year after surgery RESULT.: The mean JOA score was 6.2 points preoperatively, and 7.9, 8.2, and 8.2 points at 6 months, 1, and 2 year postoperatively, giving mean recovery rates of 35.0%, 40.9%, and 41.4% respectively. Posterior decompression and fusion with instrumentation was performed in 109 cases (48.9%). There were 45 perioperative complications in 30 cases (13.5%), with aggravation of motor disturbance in the lower extremities being most common (4.0%, n = 9). Patients treated with fusion had a significantly higher BMI, rate of gait disturbance, ossification occupation rate of OLF at CT, and intramedullary high intensity area at MRI (p < .01). The preoperative JOA score was lower (p < .05) and the JOA recovery rate at 1 year after surgery was significantly higher in cases treated without fusion (44.9% vs. 37.1%, p < .05).

CONCLUSIONS
The high rate of surgery with instrumentation of 48.9% reflects the current major trend toward posterior instrumented fusion surgery for T-OLF. Fusion surgery with instrumentation may be appropriate for patients with severe OLF and preoperative myelopathy. A further prospective study of long-term outcomes is required with a focus on optimal surgical timing and the surgical procedure for T-OPLL.

LEVEL OF EVIDENCE
3.


U.S. banking regulation has historically prohibited the ability of a bank to open or own a branch located outside of its home state, commonly referred to as interstate branching. Only since the passage of the Riegle-Neal Interstate Banking and Branching Efficiency Act (IBBEA) in 1994 have banks have been able to engage in interstate branching, though subject to state restrictions. Despite IBBEA's removal of branching barriers, it still allowed the states to impose restrictions on the entry of out-of-state branch offices. This article describes the changes in Federal and state interstate branching law since passage of IBBEA and reviews how initial (1994-1997) and evolving (1998-2004) interstate branching laws affect out-of-state branch growth. It concludes that anticompetitive state provisions restricted out-of- state growth when those provisions were more restrictive than the provisions set by IBBEA or by neighboring states.


OBJECTIVEHarvey Cushing (1869-1939) coined the term "craniopharyngioma" (CP) in 1929 to describe a kaleidoscopic group of epithelial tumors involving the hypothalamic-pituitary axis. Throughout his career, he endured a long struggle to accurately diagnose and safely remove these complex lesions, and his resulting surgical series has never before been analyzed in depth. The authors here conduct such an analysis.METHODSIn this study, the authors retrospectively examined the CP patient records available in the Cushing Brain Tumor Registry, as well as those CP cases reported by Cushing in medical monographs and scientific reports.RESULTSCushing's CP series comprises a total of 124 tumors (CP124) compatible with a CP diagnosis. Among this series are 92 cases that could be pathologically verified (CP92). This subcohort showed a bimodal age distribution (41% aged ≤ 19 years old) and a balanced sex distribution. Clinical evolution up to diagnosis was longer than 3 years in half of the patients. Typical symptoms found at diagnosis were severe headache (94%), visual deficits (97%), panhypopituitarism (76%), psychiatric disturbances (47%), and abnormal somnolence (47%). The highest rate of endocrine deficits occurred in patients younger than 19 years of age (p < 0.001), whereas hypothalamic disturbances were observed mainly in adults between 30 and 49 years (p = 0.02). Hydrocephalus was present in 63% of the patients, predominantly involving the younger subgroup (p < 0.001). Preoperative diagnosis was based on clinical signs, funduscopic exams, and skull radiographs, the latter study showing suprasellar calcifications in 64% of cases. The majority of tumors (61%) had developed within the third ventricle (3V) or had invaded it. The adamantinomatous histological variant was the predominant one (73%). Squamous-papillary CPs occurred only in adults older than 40 years of age (p < 0.001). Strong CP adherences to the hypothalamus were demonstrated in 63% of cases. The infundibulo-tuberal and sellar/suprasellar-3V CP topographies were associated with the highest rates of hypothalamic dysfunction before surgery (p < 0.001), surgical hypothalamic injury (p < 0.001), and severe postoperative morbidity and/or mortality (p = 0.009). Both topographies showed the strongest adherences to the hypothalamus and 3V (p < 0.001).CONCLUSIONSCushing's CP series comprises severely ill patients with tumors in the late stages of progression, with a high rate of tumors developing primarily within the hypothalamus (infundibulo-tuberal CPs) or invading this structure from the sellar/suprasellar regions. Craniopharyngioma topography was the fundamental variable influencing the clinical manifestations, tumor features, and patient outcomes in this series.


20 A highly diastereoselective ring-rearrangement metathesis of cyclopentene derivatives containing allcarbon quaternary centres is reported. This tandem metathesis process provides cyclohexenes derivatives with two contiguous stereogenic centres, one of which is an all-carbon quaternary stereogenic centre, in high yields and excellent diastereoselecitivity. The efficacy of this methodology is showcased in the total synthesis of spiropiperidine alkaloid nitramine. In the meantime, it has been found that metathesis of the corresponding acyclic triene derivatives affords the same products with the same level of efficiency and diastereoselectivity.


There are still many question open to completely understand the structure-activity relationships of G-protein coupled receptors. Issues like the actual mapping of the binding site of different subtypes, as well as the mechanism of activation are poorly understood [1]. Accordingly, further studies on the structure-activity relationships are necessary. In this regard, only a few 3D structures are available from X-ray diffraction studies. Computational studies can complement this information through the construction of reliable 3D models.
The goal of the present work is to evaluate the effect of using different ligands to obtain reliable models of the three-dimensional structure of a G-protein coupled receptor using a specific template. Specifically, we have constructed in the present work a three dimensional model of the M3 muscarinic receptor by homology modelling, using the X-ray structure of M2 muscarinic acetylcholine receptor as template and the sequence analyses of muscarinic acetylcholine receptor family. Furthermore, we have studied the effect of the ligand used in the modelling process. For this purpose three models of the receptor were built, including one without ligand and two models with the selective antagonists tiotropium and N-Methylscopolamine, respectively docked into the orthosteric binding site.
The constructed models were refined using molecular dynamic calculations to analyze the effect of ligand refinement process and to derive significant conformational information. Based on the analysis of the refined models done through the calculations of RMSD, RMSF, visualization of the structures and comparison between the refined models and the crystal structure of M3 muscarinic receptor, the addition of a ligand in construction of homology model (and the subsequent refinement process) stabilize the structure. Furthermore, the similarities in the structure conformations of both refined models of M3 muscarinic-ligand complexes and the crystal structure of the M3 muscarinic receptors, suggest that the methodology used in this study can be used in prediction of 3D structure prediction GPCR in the absence of crystal structures.