Although it has become a settled feature of federal courts jurisprudence, the "collateral order doctrine" first articulated by the Supreme Court in 1949 continues to provoke judicial and academic criticism. "Accordingly," as a unanimous Court stressed in 2006, "we have not mentioned applying the collateral order doctrine recently without emphasizing its modest scope," lest it come to "overpower the substantial finality interests [the final judgment rule] is meant to further."Notwithstanding the strong policy judgment enmeshed within the final judgment rule and the consistent rhetoric of the Court's collateral order opinions, this short essay demonstrates that the Justices have in fact effected a dramatic (if largely unnoticed) expansion of the collateral order doctrine in recent years — one that, by its nature, applies specifically to private suits seeking damages against government officers in their personal capacity. Starting from the now-settled holding that a government officer's official immunity is an immediately appealable collateral order (at least as to the relevant legal questions), the Court has used the obscure and obtuse doctrine of "pendent appellate jurisdiction" to sub silentio shoehorn into interlocutory appellate review of a trial court's contested denial of official immunity (1) whether the plaintiff's complaint satisfies the applicable pleading standards; (2) the elements of the plaintiff's cause of action; and (3) the very existence of such a cause of action. More to the point, these expansions have come with exceptionally little analysis, with two of these three jurisdictional holdings buried in footnotes.The practical effect of these beclouded expansions is only now becoming visible. Thus, in two recent high-profile Bivens cases, both the D.C. and Seventh Circuits (the latter sitting en banc) reversed a trial court's recognition of a Bivens claim on interlocutory appeal of the denial of qualified immunity, even though neither court of appeals disturbed the district court's underlying determination of non-immunity. And whatever might be said about the continuing viability of Bivens claims, lower courts have begun to piggyback other legal questions going to the merits onto interlocutory immunity appeals, as well. As this essay concludes, in addition to flying in the face of longstanding precedent, the more troubling analytical implication of this trend is to both formally and functionally vitiate the longstanding distinction between litigation immunities and defenses to liability. To the extent that officer defendants might now be able to press most potential legal defenses on interlocutory appeal of a denial of a motion to dismiss even where they are not entitled to official immunity, such defenses will necessarily become functional immunities from suit in any case in which they are validly invoked — and will make it that much harder (and more expensive) for plaintiffs to recover even in cases in which they are not. If the Justices truly intended such a result, even if only in officer suits, one could at least have expected them to say more about it than the cryptic discussions that have sufficed to date. Had they done so, they might have realized that such a result is incredibly difficult to defend as a matter of law, policy, precedent, or prudence.


Re-vegetation is nearly ubiquitous to stream restoration. This research examined the effects of restoration on woody riparian plant communities on temperate mountain headwater streams. We sampled 27 sites within restored, degraded, and reference groups. Data recorded were species richness, stem density, basal area, site and channel canopy cover, and channel width. Vegetation and channel structural metrics were analyzed with multivariate statistics, and community composition was examined using importance scores and ordination analysis. Restored and degraded sites had similar richness, density, basal area, canopy cover, and channel structure. Restored and reference sites had similar richness and density. Species dominance differed among all treatments. Degraded conditions were dominated by small-statured, opportunistic species. Restored sites were characterized by the shrub species used for re-vegetation and opportunistic species associated with degraded sites. At reference sites, typical regional riparian forest conditions were present. Overall species composition showed a distinct pattern for reference conditions that was different from both degraded and restored sites. Degraded and restored sites were not compositionally distinct from one another. These data suggest that these restoration projects do not yet resemble regional reference conditions. Long-term monitoring of riparian re-vegetation trajectories facilitates understanding of restoration outcomes and insures best management practice.


There is a theory which states that if ever anybody discovers exactly what the Universe is for and why it is here, it will instantly disappear and be replaced by something even more bizarre and inexplicable. There is another theory which states that this has already happened.


This Article proposes a unique resolution to the debate over political campaign participation by tax-exempt organizations, specifically religious organizations. By virtue of their tax-exempt status, these organizations are banned from participating in political campaign activity. Commentators have debated the merits of this ban for years and to say that commentators have been all over the map regarding their opinions over the ban is putting it charitably. The ban's advocates and opponents have staked out seemingly every position imaginable in arguing the merits of this ban. Some commentators have argued forcefully that the ban is needed to preserve constitutional separation of church and state. Other commentators have argued as passionately that the ban is unconstitutional and pulls at the fabric of American democracy by unduly limiting political participation by churches and religious organizations. The arguments of each side of the debate take a zero-sum gain approach to resolving the debate, and commentators seem to discount the concerns of the opposition as either irrelevant or insignificant.This Article does not attempt to resolve the debate in the literature over the ban's legitimacy. Rather, this Article proposes a solution that the literature has apparently ignored: finding a compromise between the two extremes of the debate that addresses the primary concerns of both sides. This Article proposes that section 501(c)(3) organizations be permitted an increased amount of political campaign activity in ex-change for paying a tax referred to as a "self-directed tax." What makes the self-directed tax unique is that the organizations themselves would be permitted to direct the government as to how to allocate the proceeds from the tax to a preset group of government spending choices. Similar rules would apply to the charitable deduction as well. The self-directed tax would allow section 501(c)(3) organizations to become more politically active. This Article's proposal, however, still allows section 501(c)(3) organizations to preserve their unique status as partners with government in the provision of public goods — a status that justifies not requiring them to provide a portion of their profits to the government for the government to do with as it pleases.


We review the records of published and unpublished sightings and strandings for Risso's dolphin (Grampus griseus) in subantarctic waters of the Southwestern South Atlantic Ocean. Based on 59 sighting (n = 521 individuals) and 33 stranding records (n = 88 individuals), we identified three main areas of Risso's dolphin concentration in Patagonian waters, which have been observed mostly during the austral summer. We were unable to find published or unpublished reports of Risso's dolphin in offshore or over deep-water areas in this region. Future studies covering other potential areas of the species' distribution are important to improve the scarce information known for this dolphin in this area.


This paper estimates costs associated with water pollution in the Olifants River Water Management Area (WMA) in South Africa, and, more specifically, the area represented by the Loskop Dam Water User Association. We focus on the impacts of salinisation on commercial irrigated agriculture, and of microbial pollution on the general population of the WMA, many of whom do not have access to municipal water and sanitation services, leaving them vulnerable to microbial pollution in the water resource. Costs associated with salinity are estimates based on the impacts of increased salinity on the value of marginal product of certain irrigated crops. Costs associated with microbial pollution are estimated based on the direct and indirect costs of human health impacts as a result of microbial pollution in the study area. These monetary value estimates give an indication of the magnitude of the cost of water pollution to society in the WMA. It is concluded that the once-off cost required to provide some pollution prevention infrastructure will be lower than the current annual cost burden of pollution on society in the WMA, and that pollution prevention is therefore cost effective.


Caption: This composite of 30 Doradus, aka the Tarantula Nebula, contains data from Chandra (blue), Hubble (green), and Spitzer (red). Located in the Large Magellanic Cloud, the Tarantula Nebula is one of the largest star-forming regions close to the Milky Way. Chandra's X-rays detect gas that has been heated to millions of degrees by stellar winds and supernovas. This high-energy stellar activity creates shock fronts, which are similar to sonic booms. Hubble reveals the light from massive stars at various stages of star birth, while Spitzer shows where the relatively cooler gas and dust lie.


The recent global financial crisis represented a failure of regulation to the extent that regulatory responses and strategies existed, but were not deployed, to prevent or mitigate the factors that contributed to the crisis. Recognizing the failure of regulation in preventing the recent financial crisis and the need to pursue more effective regulatory strategies, policymakers in the United Kingdom, United States and European Union set forth concurrent proposals for substantial reform of their respective regulatory systems. The reforms emphasized the reorganization of regulatory agencies and expansion of powers of surviving agencies. The proposals, however, differed significantly from each other. Successful financial regulatory reform must address four challenges. First, how should regulatory systems be structured? Second, should there be a separation of prudential supervision and consumer protection regulation? Third, which entity should be responsible for monitoring and managing systemic risk and what should be its powers? Fourth, how should cross-border financial services and transactions be supervised and regulated? The paper considers the four challenges to financial regulatory reform and evaluates whether the UK, US and EU reform proposals succeeded in addressing the challenges.Given their weaknesses, the paper concludes that the reform proposals do not go far enough to prevent future regulatory failures.


This document specifies an Internet standards track protocol for the Internet community, and requests discussion and suggestions for improvements. Please refer to the current edition of the " Internet Official Protocol Standards " (STD 1) for the standardization state and status of this protocol. Distribution of this memo is unlimited. The IESG intends to charter, in the near future, one or more working groups to produce standards for " name lookup " , where such names would include electronic mail addresses and telephone numbers, and the result of such a lookup would be a list of attributes and characteristics of the user or terminal associated with the name. Groups which are in need of a " name lookup " protocol should follow the development of these new working groups rather than using SIP for this function. In addition it is anticipated that SIP will migrate towards using such protocols, and SIP implementors are advised to monitor these efforts. Abstract The Session Initiation Protocol (SIP) is an application-layer control (signaling) protocol for creating , modifying and terminating sessions with one or more participants. These sessions include Internet multimedia conferences, Internet telephone calls and multimedia distribution. Members in a session can communicate via multicast or via a mesh of unicast relations, or a combination of these. SIP invitations used to create sessions carry session descriptions which allow participants to agree on a set of compatible media types. SIP supports user mobility by proxying and redirecting requests to the user's current location. Users can register their current location. SIP is not tied to any particular conference control protocol. SIP is designed to be independent of the lower-layer transport protocol and can be extended with additional capabilities. This document is a product of the Multi-party Multimedia Session Control (MMUSIC) working group of the Internet Engineering Task Force. Comments are solicited and should be addressed to the working group's mailing list at firstname.lastname@example.com and/or the authors.


One of the music world's pre-eminent critics takes a fresh and much-needed look at the day Dylan "went electric" at the Newport Folk Festival, timed to coincide with the event's fiftieth anniversary. On the evening of July 25, 1965, Bob Dylan took the stage at Newport Folk Festival, backed by an electric band, and roared into his new rock hit, Like a Rolling Stone. The audience of committed folk purists and political activists who had hailed him as their acoustic prophet reacted with a mix of shock, booing, and scattered cheers. It was the shot heard round the world-Dylan's declaration of musical independence, the end of the folk revival, and the birth of rock as the voice of a generation-and one of the defining moments in twentieth-century music. In Dylan Goes Electric!, Elijah Wald explores the cultural, political and historical context of this seminal event that embodies the transformative decade that was the sixties. Wald delves deep into the folk revival, the rise of rock, and the tensions between traditional and groundbreaking music to provide new insights into Dylan's artistic evolution, his special affinity to blues, his complex relationship to the folk establishment and his sometime mentor Pete Seeger, and the ways he reshaped popular music forever. Breaking new ground on a story we think we know, Dylan Goes Electric! is a thoughtful, sharp appraisal of the controversial event at Newport and a nuanced, provocative, analysis of why it matters.


Meat is a food of choice because of its nutritional quality. Grills are regularly consumed in Africa and particularly in the Sahelian countries. These are very popular consumer products. However, they can be contaminated by various microorganisms and cause food poisoning if the meat is not handled in hygienic conditions. In order to contribute to improving the quality of these products, we have followed the steps in production of meat skewers by the method of "5M" of Ishikawa. The "HACCP decision tree" model was used to determine the Critical Control Points (CCP). Hazard Analysis Critical Control Point (HACCP) is a method and principles of management of food safety. The results of monitoring procedures for making meat skewers showed many shortcomings in hygiene. Six (06) critical points were determined. As for testing, we conducted microbiological analyzes on fifty (50) units of samples corresponding to ten (10) different types of products collected at different stages of production. Compared to AFNOR (French Association of Standardization), criteria for cooked and dehydrated soups and considering the analytical variability associated with the methods of analysis, our results indicate that the products contaminated with germs indicating failure to comply with hygiene. Samples analyzed presented at different stages of production compliance rate of 40% for total bacteria (30 °C), 30% for total coliforms and thermotolerant coliforms (44 °C). The rate of non-compliance is 40% compared with sulphite-reducing anaerobes. Molds identified in meat skewered and ingredients are Aspergillus niger, Aspergillus flavus, Penicillium sp and Geotrichum sp. Salmonella, S. aureus and yeasts are absent in the samples. Training on good hygiene practices is required at vendors in order to ensure the hygienic quality of grilled meats.


What is the normative justification for individual employment law? For a number of legal scholars, the answer is economic efficiency. Other scholars argue, to the contrary, that employment law protects against (vaguely defined) imbalances of bargaining power and exploitation. Against both of these positions, this paper argues that individual employment law is best understood as advancing a particular conception of equality. That conception, which many legal and political theorists have called social equality, focuses on eliminating hierarchies of social status. Drawing on the author's work elaborating the justification for employment discrimination law, this paper argues that individual employment law is justified as preventing employers from contributing to or entrenching social status hierarchies — and that it is justifiable even if it imposes meaningful costs on employers.The paper argues that the social equality theory can help us critique, defend, elaborate, and extend the rules of individual employment law. It illustrates the point by showing how concerns about social equality, at an inchoate level, underlie some classic arguments against employment-at-will. It also shows how engaging with the question of social equality can enrich analysis of a number of currently salient doctrinal issues in employment law, including questions regarding how the law should protect workers' privacy and political speech, the proper scope of maximum-hours laws and prohibitions on retaliation, and the framework that should govern employment arbitration.


Biological warfare is a menacing twenty-first-century issue, but its origins extend to antiquity. While the recorded use of toxins in warfare in some ancient populations is rarely disputed (the use of arsenical smoke in China, which dates to at least 1000 BC, for example) the use of 'poison arrows' and other deadly substances by Native American groups has been fraught with contradiction. At last revealing clear documentation to support these theories, anthropologist David Jones transforms the realm of ethnobotany in Poison Arrows.Examining evidence within the few extant descriptive accounts of Native American warfare, along with grooved arrowheads and clues from botanical knowledge, Jones builds a solid case to indicate widespread and very effective use of many types of toxins. He argues that various groups applied them to not only warfare but also to hunting, and even as an early form of insect extermination. Culling extensive ethnological, historical, and archaeological data, Jones provides a thoroughly comprehensive survey of the use of ethnobotanical and entomological compounds applied in wide-ranging ways, including homicide and suicide. Although many narratives from the contact period in North America deny such uses, Jones now offers conclusive documentation to prove otherwise. A groundbreaking study of a subject that has been long overlooked, "Poison Arrows" imparts an extraordinary new perspective to the history of warfare, weaponry, and deadly human ingenuity.


This paper presents methods for determining the uncertainty of both differential and positive metering stations. It takes into account the type of meter, number of meters in parallel, type of secondary instruments, and the determination of physical properties. The paper then relates this information to potential influence on system balance


Book comes with the new information and lesson every time you read it. By reading the content of this book, even few, you can gain what makes you feel satisfied. Yeah, the presentation of the knowledge by reading it may be so small, but the impact will be so great. You can take it more times to know more about this book. When you have completed content of great compromise, you can really realize how importance of a book, whatever the book is


© 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Oral presentations


Microsoft Outlook 2010 is a powerful Information management application that can be used for e-mailing, but as well offers many other convenient tools. This ebook is the final part in a series of three ebooks. Part one is about folders and message options in Outlook 2010. In part two you learned about Outlook 2010 contacts and address book. In this part you will learn about tasks, notes, sharing and different tools in Outlook 2010.

A task is an assigned piece of work that must be completed within a certain time, e.g. writing a proposal or reading a report. A task can occur once or be repeated as a recurring task. A recurring task can repeat at regular intervals or based on the dates the user marks the task to be completed. By the end of the tasks chapter, you can enter and repeat tasks in Outlook 2010. Furthermore you will be able to assign tasks to other users and track tasks.

Notes are the electronic equivalent of paper sticky notes. Use notes to write down questions, ideas, reminders, and anything you would write on note paper. You can leave notes open on the screen while you work. This is especially convenient when you're using notes for storing bits of information you may need later, such as directions or text you want to reuse in other items or documents. In this chapter you will learn how to create, edit and delete notes in Outlook 2010. You as well will learn how to change the view of notes, send notes to other users and save notes on your desktop.

Just as you might have an assistant who helps you manage your incoming paper mail, Microsoft Outlook provides similar functionality by making it possible for you to give another person access to your Inbox and any other Outlook folder you want. The process of granting someone permission to open your folders, read and create items, and respond to requests for you is called assigning folder permissions. After reading the chapter 'Sharing in Outlook 2010', you will know how to delegate access, open other's calendar and share your private folders.


The credit crisis of 2008 and the subsequent collapse of a number of high-profile acquisition transactions put a spotlight on contracting practices that embedded optionality into merger agreements by way of the reverse termination fee and its attendant triggers. This article examines whether reverse termination fees are a symmetrical response to the seller's judicially-mandated fiduciary termination right and whether such fees represent an efficient transactional term. A series of Delaware cases over the last decade limited the degree to which buyers could rely on deal protection measures in merger agreements to prevent a seller from accepting a superior second bid resulting in a judicially-created fiduciary put. Where courts require seller termination rights, it is possible that buyers might attempt to negotiate symmetrical "optionality" for buyers elsewhere in the merger agreement. This article investigates whether the termination triggers that accompany reverse termination fees are that symmetrical response. Using a sample of 644 acquisitions from 2003 through 2008, which includes 105 transactions where strategic buyers negotiated a reverse termination fee, this article provides an empirical account of the use of reverse termination fees by strategic buyers, including the first taxonomy of reverse termination fee triggers. This article concludes first that reverse termination fee triggers are not a symmetrical response to the judicially mandated seller's fiduciary termination rights. Second, to the extent reverse termination rights mimic termination rights in size, they may be inefficient terms. The results of this study provide some guidance to courts as they are asked to assess the viability of reverse termination fees and the degree of optionality embedded in the modern merger agreement.


It is a truth universally acknowledged that a policeman taking a holiday would barely have had time to open his suitcase before he finds his first corpse. Commander Sam Vimes of the Ankh-Morpork City Watch is on holiday in the pleasant and innocent countryside, but not for him a mere body in the wardrobe. There are many, many bodies - and an ancient crime more terrible than murder. He is out of his jurisdiction, out of his depth, out of bacon sandwiches, occasionally snookered and out of his mind. But never out of guile. Where there is a crime there must be a finding, there must be a chase and there must be a punishment. They say that in the end all sins are forgiven. But not quite all...Winner of the Bollinger Everyman Wodehouse Prize for Comic Fiction


Uromodulin-associated kidney disease (UAKD) is caused by mutations in the uromodulin (UMOD) gene that result in a misfolded form of UMOD protein, which is normally secreted by nephrons. In UAKD patients, mutant UMOD is poorly secreted and accumulates in the ER of distal kidney epithelium, but its role in disease progression is largely unknown. Here, we modeled UMOD accumulation in mice by expressing the murine equivalent of the human UMOD p.Cys148Trp point mutation (UmodC147W/+ mice). Like affected humans, these UmodC147W/+ mice developed spontaneous and progressive kidney disease with organ failure over 24 weeks. Analysis of diseased kidneys and purified UMOD-producing cells revealed early activation of the PKR-like ER kinase/activating transcription factor 4 (PERK/ATF4) ER stress pathway, innate immune mediators, and increased apoptotic signaling, including caspase-3 activation. Unexpectedly, we also detected autophagy deficiency. Human cells expressing UMOD p.Cys147Trp recapitulated the findings in UmodC147W/+ mice, and autophagy activation with mTOR inhibitors stimulated the intracellular removal of aggregated mutant UMOD. Human cells producing mutant UMOD were susceptible to TNF-&agr;– and TRAIL-mediated apoptosis due to increased expression of the ER stress mediator tribbles-3. Blocking TNF-&agr; in vivo with the soluble recombinant fusion protein TNFR:Fc slowed disease progression in UmodC147W/+ mice by reducing active caspase-3, thereby preventing tubule cell death and loss of epithelial function. These findings reveal a targetable mechanism for disease processes involved in UAKD.


Jakob De Haan, Susanna LundstrA¶m, and Jan-Egbert Sturm have written a valuable survey of the literature that uses the Gwartney and Lawson economic freedom (EFW) index. Their discussion of the index's theoretical underpinnings and methodological ins and outs itself should be useful to scholars interested in the field. While DLS accurately describe the mechanics of the construction of the EFW index and the econometric literature that has found a link between economic freedom and economic growth, I find myself in disagreement with some of their commentary. This reply in part will address these issues.


SUMMARY Agriculture and biodiversity have often been regarded as separate concerns. Although biodiversity underpins much of modern agriculture, the development of contemporary production systems has resulted in extensive land conversion and concomitant biodiversity loss. In order to feed an ever growing population, innovative and acceptable ways of integrating biodiversity conservation and food production need to be identified. Maintaining diversity within agricultural systems is not a novel approach but one practiced by many smallholder farmers globally, in many different ways. The nutritional and livelihood benefits of diverse production systems are one way of achieving food security. Such systems are also more resilient to climate induced events or other shocks. Forests represent an important repository of food and other resources that can play a key role in contributing towards food security, especially if integrated into complex systems that are managed for multiple benefits.


Based on cellular automata (CA), the diffusion of communication products, namely the mobile phone (MP) and the landline telephone (LT), were modeled and simulated. The ordinary least squares (OLS) procedure and nonlinear regression method were carried out to estimate the diffusion parameters. The predicted results were compared with the actual data. It is found that: (1) the diffusion processes of mobile phone and landline telephone were successfully examined using cellular automata method, (2) the predicted results of mobile phone and landline telephone show four stages of the product life cycle, (3) the present situation of mobile phones in China is at the fast growth stage and the present situation of landline telephone is at the maturity stage, (4) the market of mobile communication is growing fast and has a brighter future and the landline communication market is meeting great challenges. The future competition will be more serious between the mobile communication and the landline communication. Both of them can benefit from introduction of advanced technology and new services because such a strategy has the potential to convert some consumers of one of communications into another communications. As for the whole communications, the innovation of technology and services will be generated and introduced into the industry of communications to drive the market.


In 2010, the Department of Justice (DOJ) filed a lawsuit against the credit card networks American Express, MasterCard, and Visa for alleged antitrust violations. We evaluate the extent to which the recently proposed settlement between the DOJ and Visa and MasterCard (henceforth, "Proposed Settlement") is likely to achieve its central objective: "…to allow Merchants to attempt to influence the General Purpose [Credit] Card or Form of Payment Customers select by providing choices and information in a competitive market." In word and spirit, the Proposed Settlement represents a significant step toward promoting competition in the credit card market. However, we find that merchants are unlikely to be able to take full advantage of the Proposed Settlement's new freedoms because they currently lack comprehensible and complete information on the full and exact merchant discount fees for their customers' credit cards. We analyze the likely consequences of this information problem, and consider ways in which it could be remedied. We also evaluate the probable welfare consequences of allowing merchants to impose surcharges to reflect the fees associated with the use of payment cards.


A longstanding debate, recently reinvigorated, is whether the U.S. Constitution imposes subject matter limitations on federal treatymaking akin to the limits it places, through Article I, Section 8, on federal legislation. That debate was supposedly settled in favor of substantively unlimited treatymaking power by the U.S. Supreme Court in Missouri v. Holland (1920), but leading "originalist" accounts contend that the Constitution's original meaning supports a contrary result. This essay defends Holland's conclusion against its originalist detractors, not so much as a matter of history but as a matter of methodology. It outlines and applies an approach it calls "historical textualism" as a way to determine the Constitution's original meaning. In brief, historical textualism focuses on the specific words of the Constitution's text as they were situated and understood in the context in which they were written. Among other things, historical textualism discounts structural or "framers' intent" arguments not tied to the meaning of particular phrases and abstract textual arguments not tied to understandings of particular phrases reflected in the historical record. Although receptive to arguments based on drafting, ratification and post-ratification understandings, it is most interested in how relevant phrases were used and understood prior to the Constitutional Convention or in contexts not directly implicating the particular controversy at issue. Applying this idea of historical textualism, this essay finds that the Constitution's original meaning finds fully supports Holland's conclusion that the treatymaking power is not substantively limited. Its contrast with other originalist analyses finding subject matter limits on federal treatymaking underscores the differences between historical textualism other approaches for determining historical meaning.


Dear Brothers in the Episcopate, distinguished Ladies and Gentlemen. Organ donation is a peculiar form of witness to charity. In a period like ours, often marked by various forms of selfishness, it is ever more urgent to understand how the logic of free giving is vital to a correct conception of life. Indeed, a responsibility of love and charity exists that commits one to make of their own life a gift to others, if one truly wishes to fulfil oneself. As the Lord Jesus has taught us, only whoever gives his own life can save it (cf. Lk 9:24). In greeting all those present, with particular thought for Senator Maurizio Sacconi, Minister of Labour, Health and Social Policies, I thank Archbishop Rino Fisichella, President of the Pontifical Academy for Life, for the words he has addressed to me illustrating the profound meaning of this meeting and presenting the synthesis of the Congress' works. Together with him I also thank the President of the International Federation of Catholic Medical Associations and the Director of the Centro Nazionale Trapianti, underlining my appreciation of the value of the collaboration of these Organizations in an area like that of organ transplants which, distinguished Ladies and Gentlemen, has been the object of your days of study and debate. Medical history clearly shows the great progress that it has been possible to accomplish to ensure to each person who suffers an ever more worthy life. Tissue and organ transplants represent a great victory for medical science and are certainly a sign of hope for many patients who are experiencing grace and sometimes extreme clinical situations. If we broaden our gaze to the entire world it is easy to identify the many and complex cases in which, thanks to the technique of the transplantation of organs, many people have survived very critical phases and have been restored to the joy of life. This could never have happened if the committed doctors and qualified researchers had not been able to count on the generosity and altruism of those who have donated their organs. The problem of the availability of vital organs to transplant, unfortunately, is not theoretic, but dramatically practical; it is shown by the long waiting lists of many sick people whose sole possibility for survival is linked to the meagre offers that do not correspond to the objective need. It is helpful, above all in today's context, to return to reflect on this scientific breakthrough, to prevent the multiple requests for transplants from subverting the ethical principles that are at its base. As I said in my first Encyclical, the body can never be considered a mere object (cf. Deus Caritas Est, n. 5); otherwise the logic of the market would gain the upper hand. The body of each person, together with the spirit that has been given to each one singly constitutes an inseparable unity in which the image of God himself is imprinted. Prescinding from this dimension leads to a perspective incapable of grasping the totality of the mystery present in each one. Therefore, it is necessary to put respect for the dignity of the person and the protection of his/her personal identity in the first place. With regards to the practice of organ transplants, it means that someone can give only if he/she is not placing his/her own health and identity in serious danger, and only for a morally valid and proportional reason. The possibility of organ sales, as well as the adoption of discriminatory and utilitarian criteria, would greatly clash with the underlying meaning of the gift that would place it out of consideration, qualifying it as a morally illicit act. Transplant abuse and their trafficking, which often involves innocent people, like babies, must find the scientific and medical community ready to unite in rejecting such unacceptable practices. Therefore they are to be decisively condemned as abominable. The same ethical principle is to be repeated when one wishes to touch upon creation and destroy the human embryo destined for a therapeutic purpose. The simple idea of considering the embryo as "therapeutic material" contradicts the cultural, civil and ethical foundations upon which the dignity of the person rests. It often happens that organ transplantation techniques take place with a totally free act on the part of the parents of patients in which death has been certified. In these cases, informed consent is the condition, the subject to freedom, for the transplant to have the characteristic of a gift and is not to be interpreted as an act of coersion or exploitation. It is helpful to remember, however, that the individual vital organs cannot be extracted except ex cadavere, which, moreover, possesses its own dignity that must be respected. In these years science has accomplished further progress in certifying the death of the patient. It is good, therefore, that the results attained receive the consent of the entire scientific community in order to further research solutions that give certainty to all. In an area such as this, in fact, there cannot be the slightest suspicion of arbitration, and where certainty has not been attained the principle of precaution must prevail. This is why it is useful to promote research and interdisciplinary reflection to place public opinion before the most transparent truth on the anthropological, social, ethical and juridical implications of the practice of transplantation. However, in these cases the principal criteria of respect for the life of the donor must always prevail so that the extraction of organs be performed only in the case of his/her true death (cf. Compendium of the Catechism of the Catholic Church, n. 476). The act of love which is expressed with the gift of one's vital organs remains a genuine testimony of charity that is able to look beyond death so that life always wins. The recipient of this gesture must be well aware of its value. He/she is the receiver of a gift that goes far beyond the therapeutic benefit. In fact, what he/she received, before being an organ, is a witness of love that must raise an equally generous response, so as to increase the culture of gift and gratuity. The right road to follow, until science is able to discover other new forms and more advanced therapies, must be the formation and the spreading of a culture of solidarity that is open to all and does not exclude anyone. A medical transplantation corresponds to an ethic of donation that demands on the part of the commitment to


There are now a number of BIDIRECTIONAL PROGRAMMING LANGUAGES, where every program can be read both as a forward transformation mapping one data structure to another and as a reverse transformation mapping an edited output back to a correspondingly edited input. Besides parsimony - the two related transformations are described by just one expression - such languages are attractive because they promise strong behavioral laws about how the two transformations fit together - e.g., their composition is the identity function. It has repeatedly been observed, however, that such laws are actually a bit too strong: in practice, we do not want them "on the nose," but only up to some equivalence, allowing inessential details, such as whitespace, to be modified after a round trip. Some bidirectional languages loosen their laws in this way, but only for specific, baked-in equivalences.
 In this work, we propose a general theory of QUOTIENT LENSES - bidirectional transformations that are well behaved modulo equivalence relations controlled by the programmer. Semantically, quotient lenses are a natural refinement of LENSES, which we have studied in previous work. At the level of syntax, we present a rich set of constructs for programming with CANONIZERS and for quotienting lenses by canonizers. We track equivalences explicitly, with the type of every quotient lens specifying the equivalences it respects.
 We have implemented quotient lenses as a refinement of the bidirectional string processing language Boomerang. We present a number of useful primitive canonizers for strings, and give a simple extension of Boomerang's regular-expression-based type system to statically typecheck quotient lenses. The resulting language is an expressive tool for transforming real-world, ad-hoc data formats. We demonstrate the power of our notation by developing an extended example based on the UniProt genome database format and illustrate the generality of our approach by showing how uses of quotienting in other bidirectional languages can be translated into our notation.


The investigation of OER initiatives requires rigorous appraisal based on theory as well as descriptions based on practice if we are to understand them and how they might be sustained. A robust typology or flexible classification scheme will enable better comparison of common elements over widely different OER initiatives and help inform and improve praxis at all levels and across all socio-economic and cultural systems. This in turn will help the variety of stakeholders to better understand what is happening and why. This paper describes how a typology was used between 2008 and 2010 to investigate three different OER initiatives in Sub Saharan Africa. The typology was first developed by careful scrutiny of the many OER and OERrelated initiatives both globally and in Sub Saharan African. The typology was then both tested and further developed and refined by applying it to the TESSA, Thutong Portal and Rip, Mix, Learn initiatives. The typology uses four main categories – creation, organisation, dissemination and utilisation – and 18 sub categories to examine and analyse each initiative, with each sub category having a number of properties and possible dimensions. The data that informed this process included interviews with key personnel and the coding of a large body of white and grey literature and documentation produced by the initiatives themselves. This typology can thus be used to distinguish one type of OER initiative from another while grounding each in a wider context. For example, initially TESSA concentrated almost entirely on the "creation of OER" while the Thutong Portal concentrated on the "Organisation of OER" in that it spent a great deal of time and energy on the portal storage mechanisms. In other words the elements included in the Typology can be used to describe or "profile" initiatives regardless of their particular emphasis or approach. None of the initiatives need possess all of the elements contained in the typology as long as they have all been considered. As there are different levels of categorisation the typology is simple at the highest level, with just four elements, for use by practitioners; but is detailed enough at other levels to enable researchers to generate research questions. Furthermore the typology is flexible enough to evolve over time as it is applied to more and more OER initiatives both within and outside Africa and also as existing initiatives change and develop over time and while new initiatives emerge. Indeed the relative immaturity of the case study initiatives used to test and refine the typology was a concern for both practitioners and researchers and it is no surprise that the studies main findings were that (a) greater investment was needed in capacity building, (b) more attention given to appropriate use of technology and pedagogy in higher educational systems and (c) more contextual research applicable to sub Saharan Africa to inform those decisions.


The book argues that personal archives might be assuming a new importance in society. As the technical means for creating, maintaining, and using documents are improving and becoming more cost-effective, individuals and families are seeking to preserve their old documents, especially traditional paper forms, as a connection to a past that may seem to be in risk of being of being swallowed up in the immense digital gadgetry in our Internet Age. There is a reversal to other technologies as well, such as leather bound journals and fountain pens, by some individuals resisting or protesting the increasingly digital world they reside in. Behind these very different approaches are similar impulses, and, these divergent paths raise identical questions about the role and purpose of traditional archives dating back two centuries and more. Personal recordkeeping raises an array of issues and concerns about records and their preservation, public or collective memory, the mission of professional records managers and archivists, the nature of the role of the institutional archives, and the function of the individual citizen as their own archivist. Archivists need to develop a new partnership with the public, and the public needs to learn from the archivists the essentials of preserving documentary materials. We are on the cusp of seeing a new kind of archival future, and whether this is good or bad depends on how well archivists equip citizen archivists.


Information architecture (IA) is far more challengingand necessarythan ever. With the glut of information available today, anything your organization wants to share should be easy to find, navigate, and understand. But the experience you provide has to be familiar and coherent across multiple interaction channels, from the Web to smartphones, smartwatches, and beyond.To guide you through this broad ecosystem, this popular guidenow in its fourth editionprovides essential concepts, methods, and techniques for digital design that have withstood the test of time. UX designers, product managers, developers, and anyone involved in digital design will learn how to create semantic structures that will help people engage with your message.This book includes:An overview of IA and the problems it solves for creating effective digital products and servicesA deep dive into IA components, including organization, labeling, navigation, search, and metadataProcesses and methods that take you from research to strategy, design, and IA implementation


The role of genetic inheritance dominates current evolutionary theory. At the end of the nineteenth century, however, several evolutionary theorists independently speculated that learned behaviors could also affect the direction and rate of evolutionary change. This notion was called the Baldwin effect, after the psychologist James Mark Baldwin. In recent years, philosophers and theorists of a variety of ontological and epistemological backgrounds have begun to employ the Baldwin effect in their accounts of the evolutionary emergence of mind and of how mind, through behavior, might affect evolution. The essays in this book discuss the originally proposed Baldwin effect, how it was modified over time, and its possible contribution to contemporary empirical and theoretical evolutionary studies. The topics include the effect of the modern evolutionary synthesis on the notion of the Baldwin effect, the nature and role of niche construction in contemporary evolutionary theory, the Baldwin effect in the context of developmental systems theory, the possible role of the Baldwin effect in computational cognitive science biosemiotics, and the emergence of consciousness and language.


A must read for all developers that want to begin serious Android development. Justin Anderson, Freelance Android Developer From start to finish, this book contains a variety of great tips and insight into the most important attributes of Android design. This book will definitely be required reading for any of our future Android engineers. Cameron Banga, Cofounder, 9magnets, LLC Theres a downside to Androids amazing openness and versatility: its easy for developers to write code thats inefficient, unreliable, insecure, or hard to maintain. In Android Development Patterns , enterprise Android developer Phil Dutson helps you leverage Android 5.0+s amazing power without falling victim to those pitfalls. Dutson presents todays most comprehensive set of patterns and procedures for building optimized, robust apps with Android 5.0+. First, Dutson guides you through establishing a highly efficient development environment and workflow, and testing your app to ensure that your code works just as you expect. Then, he walks through the modern best practices for structuring apps, using widgets and components, and working with views. You learn how to build apps that are easy to manage and update, deliver accurate and up-to-date information without wasting precious battery power, and take advantage of new hardware, such as Android Wear and Android TV. Dutson concludes by presenting powerful strategies for optimizing your apps and packaging them for distribution. Coverage includes Using testing to build more trustworthy, dependable, maintainable apps Understanding subtle but critical differences between Android and traditional Java programming Building consistent, modern user interfaces with views and layouts Leveraging the proven MVC pattern to cleanly organize logic Creating rich visual experiences with 3D graphics, animation, and media Simplifying capture and use of location data with the new Locations API Integrating optional hardware, such as Bluetooth, NFC, or USB Building better apps with Google Play Services Creating Android Wear notifications and apps Tuning and improving apps with Google Analytics Designing Android TV apps for the ten foot view informit.com/aw https://github.com/dutsonpa/adp-files


Energy systems integration (ESI) enables the effective analysis, design, and control of these interactions and interdependencies along technical, economic, regulatory, and social dimensions. By focusing on the optimization of energy from all systems, across all pathways, and at all scales, we can better understand and make use of the co-benefits that result to increase reliability and performance, reduce cost, and minimize environmental impacts. This white paper discusses systems integration and the research in new control architectures that are optimized at smaller scales but can be aggregated to optimize energy systems at any scale and would allow replicable energy solutions across boundaries of existing and new energy pathways.


A review of:

Silverstein, Joanne. "Just Curious: Children's Use of Digital Reference for Unimposed Queries and Its Importance in Informal Education." Library Trends 54.2 (Fall 2005): 228-44.

Objective – To determine 1) how and with what frequency children use digital references to answer their own unimposed questions; 2) whether digital reference services support their self-initiated learning; 3) whether digital reference services support the transfer of student motivation and curiosity from the formal to the informal; and 4) what instructional and software designers should consider in creating tools that support learning.

Design – Inductive analysis.

Setting – Virtual Reference Desk's (VRD) Learning Center (http://vrd.askvrd.org/) and the National Science Foundation's (NSF) digital reference service (http://www.esteme.org) during Excellence in Science, Technology, Engineering, and Mathematics Education Week (ESTEME), April 11-16, 2005.

Subjects – Elementary (K-5), middle (6-8), and high school (9-12) students from the general public. One hundred fourteen questions were analyzed, however there is no indication of the number of different students who submitted the questions.

Methods – This study was conducted using a pool of 600 questions from students, teachers, parents, and the general public that were submitted to two digital reference services intended for students. Three hundred experts in the fields of Math and Science volunteered to answer the submitted questions during Excellence in Science, Technology, Engineering, and Mathematics Education Week. Because the digital services employed a pull-down menu to describe the user as a student, teacher, parent, etc., the questions could be narrowed to those submitted by students. The questions were also narrowed to those marked as "just curious" from a question purpose menu that contained categories including "written report," "science fair project," and "just curious." A total of 114 unique questions from elementary, middle, and high school students were analyzed to determine the study objectives. The 114 questions were loaded into a qualitative software application (HyperResearch) for inductive analysis. Questions from students were coded as elementary, middle, or high school and only those questions derived from students' self-initiated interests were analyzed.

Main results – Analysis revealed that elementary students submitted a large portion of the questions. Middle school students asked the most questions, of which some questions were compound (more than one question in a given query). Older students submitted the least amount of questions. an unanticipated finding was that students' grade levels correlated to the foci of their queries, which regarded "My Life," "My Stuff," "Other People," "The World," "The Universe," or "Abstract Thought." High school students were interested in the narrowest foci pertaining to their immediate circumstance rather than the larger topics of other people, the world, and the universe. The majority of middle school students were interested in abstract concepts, and 45% of elementary school students' queries were about how the world works. Although this study was not longitudinal, results suggest that student curiosity may shift over time. Results also indicated that younger children demonstrated interests outside the classroom that were related to formal learning previously introduced within the classroom. This carry over of interest declined in upper grades. Queries that were unimposed but related to an academic subject such as science or social studies were most evident in questions submitted by elementary students, while questions dealing more with career planning, health, death, and anxiety were most frequently addressed by middle school students. The findings also indicated that the use of digital reference services is at its highest in elementary school, peaks in middle school, and falls drastically in high school.

Conclusion – 1) How and with what frequency do children use digital reference services to answer their own unimposed questions? The results of this study revealed a trend on the frequency and purpose of use of digital references when seeking answers to self-initiated questions. Elementary students tend to use the digital reference services more often and for answers to questions that may be related to classroom curriculum. Middle school students utilize digital references to look for information pertaining to careers, health and welfare, death and anxiety. High school students submitted questions pertaining to their immediate circumstances ("My Life and My World") rather than focusing on others. 2) Do digital reference services support self-initiated learning? Of the original 2,258 questions submitted, 13% were considered "informal." These findings indicate that digital reference services support self-initiated learning. 3) Could digital reference services support the transfer of student motivation and curiosity from formal to informal education and learning? The frequency of questions from elementary students that were coded as "Curriculum Related Interest" leads one to conclude that digital reference services can indeed support the transfer of student interest from formal to informal education. 4) What should instructional and software designers consider when creating tools that support the notion of transformed education and learning? Although it is impossible to actually know the nature of the difficulties experienced by users, duplicate questions from the same user were received by the reference services, which suggests that the user may be experiencing difficulty with the software or that the software may actually be malfunctioning during usage. Compound questions were also frequently submitted. Software designers should take note of these findings to design services that are age-appropriate, especially regarding the type of questions each age group tends to ask, and that support the needs of elementary, middle, and high school students. Software designers should perhaps even consult with students who use these services during the design process.


Even today, as trendy diets and a weight-loss frenzy sweep the nation, two-thirds of adults are still obese and children are being diagnosed with Type 2 diabetes, typically an "adult" disease, at an alarming rate. If we're obsessed with being thin more so than ever before, why are Americans stricken with heart disease as much as we were 30 years ago? In The China Study, Dr. T. Colin Campbell details the connection between nutrition and heart disease, diabetes, and cancer. The report also examines the source of nutritional confusion produced by powerful lobbies, government entities, and opportunistic scientists. The New York Times has recognized the study as the "Grand Prix of epidemiology" and the "most comprehensive large study ever undertaken of the relationship between diet and the risk of developing disease." The China Study is not a diet book. Dr. Campbell cuts through the haze of misinformation and delivers an insightful message to anyone living with cancer, diabetes, heart disease, obesity, and those concerned with the effects of aging. [This book is also available in Spanish, El Estudio de China.]


Nigeria is still characterized by high reliance on food imports. Malnutrition is widespread in the entire country and rural areas are especially vulnerable to chronic food shortages, malnutrition, unbalanced nutrition, erratic food supply, poor quality foods, high food costs, and even total lack of food. This phenomenon cuts across all age groups and categories of individuals in the rural areas. There is a high level of malnutrition among children in rural Nigeria; the figures differ with geopolitical zones, with 56 percent reported in a rural area of South West and 84.3 percent in three rural communities in the northern part of Nigeria. Nationally, the overall prevalence of stunting, wasting, and underweight are 42.0 percent, 9 percent and 25 percent, respectively. The problem of food and nutrition security in Nigeria has not been adequately and critically analyzed, despite various approaches at addressing the challenge. The enormous amount of money spent in attempting to assure the food security of Nigerians without success calls for a fundamental review of the past approaches and achievements to see what lessons can be learned to re-strategize and develop an approach that will ensure that better progress is made toward achieving the first Millennium Development Goal. Since the majority of Nigerians (70 percent) live in rural areas, an analysis of the food and nutrition security status of rural dwellers will provide a clear picture of what needs to be done to assure food security in Nigeria with the attendant improvements in nutrition status when all the other necessary conditions, such as adequate health and care, are present. The main objective of this knowledge review was to collect and summarize available secondary literature on food and nutrition security in rural Nigeria. The framework for the analysis of food and nutrition security details the factors responsible for low consumption of food and resulting malnutrition. The socioeconomic and political environment at the national and subnational level is the principal determinant of food security, since it influences food availability, stability of food supplies, and access to food, which in turn influence the amount of food consumed. When these factors interact with the health and sanitation environment as well as care practices they determine the nutritional status of the individual. There is a dearth of national surveys providing datasets for the analysis of food and nutrition security in rural Nigeria. Though there have been a number of individual and institutional efforts and attempts at generating databases on food and nutrition security for Nigeria, these efforts are hampered by inadequate funds to implement large-scale surveys. Fundamentally, we find that food insecurity and malnutrition in rural areas of Nigeria result from non implementation and/or faulty implementation of the National Food and Nutrition Policy and National Plan of Action for Food and Nutrition. Other reasons identified include unacceptably high levels of poverty in rural households, low priority for nutrition on the agenda of government and resulting poor funding, poor understanding by policymakers of the content of nutrition programs in relation to other sectors, poor infant and child feeding practices, inadequate access to healthy environment and health services as well as various care practices. The review concludes that the existing knowledge of food and nutrition security in rural areas of Nigeria does not offer detailed information to the household level, at which greater understanding is required to help design interventions that will change the unacceptable food and nutrition situation of rural dwellers in Nigeria. This gap needs to be filled to make progress in changing the food and nutrition security situation of rural dwellers in Nigeria. Identified gaps in knowledge include the issue of mainstreaming nutrition considerations and activities into poverty reduction, agricultural development policies, and food security interventions. There is a need to understand and appreciate the distinctness of nutrition and prioritize its appropriate integration into all sectors and departments working on food security in Nigeria. Similarly, knowledge of the impact of seasonal variations, the environment, and livelihoods on food usage, consumption patterns, food coping strategies, and food and nutrition security status is important for action in Nigeria. The knowledge gaps also include understanding the interconnectedness of gender factors and their roles in achieving household food and nutrition security, and understanding the impact of an integrated approach such as the integration of gender, environment, nutrition and agricultural activities, in achieving livelihoods for women, household food and nutrition security. The review recommends a strategic partnership and collaboration of all stakeholders to produce datasets that will allow for new directions and a plan of action to seek a comprehensive integration of nutrition and coordination of food security interventions among all partners at all levels, particularly in government ministries and agencies. This multi-stakeholder and multidimensional approach is required for an effective mainstreaming, integration and coordination of food and nutrition activities.


Part I Business Analysis and Requirements of IP/MPLS VPN Chapter 1 Assessing Enterprise Legacy WANs and IP/VPN Migration Current State of Enterprise Networks Evolutionary Change of Enterprise Networks Acme, a Global Manufacturer Acme's Global Span Business Desires of Acme's Management Acme's IT Applications Base Acme's IT Communications Infrastructure New WAN Technologies for Consideration by Acme Layer 3 IP/MPLS VPN Services Layer 2 IP/MPLS VPN Services Convergence Services Internet Access Mobile Access and Teleworker Access Voice Services: Service Provider Hosted PSTN Gateway Voice Services: Service Provider Hosted IP Telephony Summary Chapter 2 Assessing Service Provider WAN Offerings Enterprise/Service Provider Relationship and Interface Investigation Required in Selecting a Service Provider Coverage, Access, and IP Financial Strength of the Service Provider Convergence Transparency IP Version 6 Provider Cooperation/Tiered Arrangements Enhanced Service-Level Agreement Customer Edge Router Management Service Management Customer Reports and SLA Validation Summary Chapter 3 Analyzing Service Requirements Application/Bandwidth Requirements Backup and Resiliency Enterprise Segmentation Requirements Mapping VLANs to VPNs in the Campus Access Technologies Frame Relay ATM Dedicated Circuit from CE to PE ATM PVC from CE to PE Frame Relay PVC from CE to PE Metro Ethernet QoS Requirements Bandwidth Packet Delay and Jitter Packet Loss Enterprise Loss, Latency, and Jitter Requirements QoS at Layer 2 Subscriber Network QoS Design Baseline New Applications Develop the Network Security Requirements Topological and Network Design Considerations SP-Managed VPNs Multiprovider Considerations Extranets Case Study: Analyzing Service Requirements for Acme, Inc. Layer 2 Description Existing Customer Characteristics That Are Required in the New Network DefenseCo's Backbone Is a Single Autonomous System Reasons for Migrating to MPLS Evaluation Testing Phase Routing Convergence Jitter and Delay Congestion, QoS, and Load Testing Vendor Knowledge and Technical Performance Evaluation Tools TTCP Lessons Learned Transition and Implementation Concerns and Issues Post-Transition Results Summary References Part II Deployment Guidelines Chapter 4 IP Routing with IP/MPLS VPNs Introduction to Routing for the Enterprise MPLS VPN Implementing Routing Protocols Network Topology Addressing and Route Summarization Route Selection Convergence Network Scalability Memory CPU Security Site Typifying WAN Access: Impact on Topology Site Type: Topology WAN Connectivity Standards Site Type A Attached Sites: Dual CE and Dual PE Site Type B/3 Dual-Attached Site--Single CE, Dual PE Site Type B/3 Dual-Attached Site--Single CE, Single PE Site Type D Single-Attached Site--Single CE with Backup Convergence: Optimized Recovery IP Addressing Routing Between the Enterprise and the Service Provider Using EIGRP Between the CE and PE How EIGRP MPLS VPN PE-to-CE Works PE Router: Non-EIGRP-Originated Routes PE Router: EIGRP-Originated Internal Routes PE Router: EIGRP-Originated External Routes Multiple VRF Support Extended Communities Defined for EIGRP VPNv4 Metric Propagation Configuring EIGRP for CE-to-PE Operation Using BGP Between the CE and PE Securing CE-PE Peer Sessions Improving BGP Convergence Case Study: BGP and EIGRP Deployment in Acme, Inc. Small Site--Single-Homed, No Backup Medium Site--Single-Homed with Backup Medium Site--Single CE Dual-Homed to a Single PE Large Site--Dual-Homed (Dual CE, Dual PE) Load Sharing Across Multiple Connections Very Large Site/Data Center--Dual Service Provider MPLS VPN Site Typifying Site Type A Failures Solutions Assessment Summary References Cisco Press Chapter 5 Implementing Quality of Service Introduction to QoS Building a QoS Policy: Framework Considerations QoS Tool Chest: Understanding the Mechanisms Classes of Service Hardware Queuing Software Queuing QoS Mechanisms Defined Pulling It Together: Build the Trust Building the Policy Framework Classification and Marking of Traffic Trusted Edge Device Trust Application Trust CoS and DSCP Strategy for Classifying Voice Bearer Traffic QoS on Backup WAN Connections Shaping/Policing Strategy Queuing/Link Efficiency Strategy IP/VPN QoS Strategy Approaches for QoS Transparency Requirements for the Service Provider Network QoS CoS Requirements for the SP Network WRED Implementations Identification of Traffic What Would Constitute This Real-Time Traffic? QoS Requirements for Voice, Video, and Data QoS Requirements for Voice QoS Requirements for Video QoS Requirements for Data The LAN Edge: L2 Configurations Classifying Voice on the WAN Edge Classifying Video on the WAN Edge Classifying Data on the WAN Edge Case Study: QoS in the Acme, Inc. Network QoS for Low-Speed Links: 64 kbps to 1024 kbps QoS Reporting Summary References Chapter 6 Multicast in an MPLS VPN Introduction to Multicast for the Enterprise MPLS VPN Multicast Considerations Mechanics of IP Multicast RPF Source Trees Versus Shared Trees Protocol-Independent Multicast Interdomain Multicast Protocols Source-Specific Multicast Multicast Addressing Administratively Scoped Addresses Deploying the IP Multicast Service Default PIM Interface Configuration Mode Host Signaling Sourcing Multicast Deployment Models Any-Source Multicast Source-Specific Multicast Enabling SSM 206 Multicast in an MPLS VPN Environment: Transparency Multicast Routing Inside the VPN Case Study: Implementing Multicast over MPLS for Acme Multicast Addressing Multicast Address Management Predeployment Considerations MVPN Configuration Needs on the CE Boundary ACL Positioning of Multicast Boundaries Configuration to Apply a Boundary Access List Rate Limiting MVPN Deployment Plan Preproduction User Test Sequence What Happens When There Is No MVPN Support? Other Considerations and Challenges Summary References Chapter 7 Enterprise Security in an MPLS VPN Environment Setting the Playing Field Comparing MPLS VPN Security to Frame Relay Networks Security Concerns Specific to MPLS VPNs Issues for Enterprises to Resolve When Connecting at Layer 3 to Provider Networks History of IP Network Attacks Strong Password Protection Preparing for an Attack Identifying an Attack Initial Precautions Basic Attack Mitigation Basic Security Techniques Remote-Triggered Black-Hole Filtering Loose uRPF for Source-Based Filtering Strict uRPF and Source Address Validation Sinkholes and Anycast Sinkholes Backscatter Traceback Cisco Guard Distributed DoS, Botnets, and Worms Anatomy of a DDoS Attack Botnets Worm Mitigation Case Study Selections Summary References Comparing MPLS VPN to Frame Relay Security ACL Information Miscellaneous Security Tools Cisco Reference for MPLS Technology and Operation Cisco Reference for Cisco Express Forwarding Public Online ISP Security Bootcamp Tutorials, Workshops, and Bootcamps Original Backscatter Traceback and Customer-Triggered Remote- Triggered Black-Hole Techniques Source for Good Papers on Internet Technologies and Security Security Work Definitions NANOG SP Security Seminars and Talks Birds of a Feather and General Security Discussion Sessions at NANOG Chapter 8 MPLS VPN Network Management The Enterprise: Evaluating Service Provider Management Capabilities Provisioning SLA Monitoring Fault Management Reporting Root Cause Analysis The Enterprise: Managing the VPN Planning Ordering Provisioning Monitoring Optimization The Service Provider: How to Meet and Exceed Customer Expectations Provisioning Fault Monitoring OAM and Troubleshooting Fault Management SLA Monitoring Reporting Summary References Chapter 9 Off-Net Access to the VPN Remote Access Dial Access via RAS Dial Access via L2TP Connecting L2TP Solutions to VRFs DSL Considerations Cable Considerations IPsec Access GRE + IPsec on the CPE CE-to-CE IPsec The Impact of Transporting Multiservice Traffic over IPsec Split Tunneling in IPsec Supporting Internet Access in IP VPNs Case Study Selections Summary References General PPP Information Configuring Dial-In Ports L2TP Layer 2 Tunnel Protocol Fact Sheet Layer 2 Tunnel Protocol VPDN Configuration Guide VPDN Configuration and Troubleshooting Security Configuration Guide RADIUS Configuration Guide Broadband Aggregation to MPLS VPN Remote Access to MPLS VPN Network-Based IPsec VPN Solutions IPsec GRE + IPsec DMVPN Split Tunneling Prefragmentation 373 Chapter 10 Migration Strategies Network Planning Writing the RFP Architecture and Design Planning with the Service Providers Project Management SLAs with the Service Providers Network Operations Training Implementation Planning Phase 1 Phase 2 Phase 3 Phase 4 On-Site Implementation Case Study Selections Summary Part III Appendix Appendix Questions to Ask Your Provider Regarding Layer 3 IP/MPLS VPN Capability 1587051915TOC012406


Increasing militant activity in western Pakistan poses three key national security threats: an increased potential for major attacks against the United States itself; a growing threat to Pakistani stability; and a hindrance of U.S. efforts to stabilize Afghanistan. This report addresses this issue at length. It also describes the recent upsurge of militant activity on the Pakistani side of the Pakistan-Afghanistan border, as well as the general political climates of Pakistan and Afghanistan and their relationships with the United States.


Jerry Brotton is the presenter of the acclaimed BBC4 series "Maps: Power, Plunder and Possession". Here he tells the story of our world through maps. Throughout history, maps have been fundamental in shaping our view of the world, and our place in it. But far from being purely scientific objects, world maps are unavoidably ideological and subjective, intimately bound up with the systems of power and authority of particular times and places. Mapmakers do not simply represent the world, they construct it out of the ideas of their age. In this scintillating book, Jerry Brotton examines the significance of 12 maps - from the mystical representations of ancient history to the satellite-derived imagery of today. He vividly recreates the environments and circumstances in which each of the maps was made, showing how each conveys a highly individual view of the world - whether the Jerusalem-centred Christian perspective of the 14th century Hereford Mappa Mundi or the Peters projection of the 1970s which aimed to give due weight to 'the third world'. Although the way we map our surroundings is once more changing dramatically, Brotton argues that maps today are no more definitive or objective than they have ever been - but that they continue to make arguments and propositions about the world, and to recreate, shape and mediate our view of it. Readers of this book will never look at a map in quite the same way again.


This thesis presents an analysis of API usage in a large corpus of Java software retrieved from the open source repositories hosted at SourceForge. Most larger software projects use software libraries, which offer a public "application programming interface" or API as an interface for the programmer. In order to facilitate the transition between different APIs, there are emerging research projects in the field of automated API migration. However, there is a lack of basic statistical background information about in-the-wild usage of APIs as such measurements have, until now, only been done on rather small corpora. We thus present an analysis method suitable for measurements with large corpora. First, we create a corpus of open source projects hosted on SourceForge, as well as a corpus of software libraries. Then, all projects in the corpus are compiled with an instrumented compiler. We use a compiler plugin for javac that gives detailed information about every method created by the compiler. This information is stored in a database and analyzed.


Many readers have noted the abundant references to law in Shakespeare's Hamlet. Indeed, a whole sub-genre of criticism has developed around the question of whether Shakespeare's knowledge of law, as reflected in this play and others, is detailed and extensive enough to indicate legal training. These critics, however, have so far lacked scholarly backgrounds in Early Modern English literature and culture, and thus fail to connect the legal language and themes of the play to its other concerns about gender and rule. By the same token, literature scholars writing about the play have lacked backgrounds in English legal history. Bringing both perspectives to bear, I show that the play's legal allusions are closely related to its other concerns about gender, and that these themes in turn partake of changes in the broader culture, namely, the end of the forty-year reign of Elizabeth, a woman ruler, and an ensuing backlash against female political power. In sum, I will show that placing the play's legal references in context reveals that they are part of a process of ejecting the feminine from the political realm.


The inspirational tale of eight women who defied the confines of life in revolutionary Iran through the joy and power of literature. 'That room for all of us, became a place of transgression. What a wonderland it was! Sitting around the large coffee table covered with bouquets of flowers ...We were, to borrow from Nabokov, to experience how the ordinary pebble of ordinary life could be transformed into a jewel through the magic eye of fiction.' For two years before she left Iran in 1997, Azar Nafisi gathered seven young women at her house every Thursday morning to read and discuss forbidden works of Western literature. They were all former students whom she had taught at university. Some came from conservative and religious families, others were progressive and secular; several had spent time in jail. Shy and uncomfortable at first, they soon began to open up and speak more freely, not only about the novels they were reading but also about themselves, their dreams and disappointments. Their stories intertwined with those they were reading - 'Pride and Prejudice', 'Washington Square', 'Daisy Miller' and 'Lolita' - their Lolita, as they imagined her in Tehran. Nafisi's account flashes back to the early days of the revolution when she first started teaching at the University of Tehran amid the swirl of protests and demonstrations. In those frenetic days, the students took control of the university, expelled faculty members and purged the curriculum. Azar Nafisi's luminous tale offers a fascinating portrait of the Iran-Iraq war viewed from Tehran and gives us a rare glimpse, from the inside, of women's lives in revolutionary Iran. It is a work of great passion and poetic beauty, written with a startlingly original voice.


Attribution of the causes of atmospheric trace gas and aerosol variability often requires the use of high resolution time series of anthropogenic and natural emissions inventories. Here we developed an approach for representing synoptic- and diurnal-scale temporal variability in fire emissions for the Global Fire Emissions Database version 3 (GFED3). We disaggregated monthly GFED3 emissions during 2003–2009 to a daily time step using Moderate Resolution Imaging Spectroradiometer (MODIS)-derived measurements of active fires from Terra and Aqua satellites. In parallel, mean diurnal cycles were constructed from Geostationary Operational Environmental Satellite (GOES) Wildfire Automated Biomass Burning Algorithm (WF_ABBA) active fire observations. Daily variability in fires varied considerably across different biomes, with short but intense periods of daily emissions in boreal ecosystems and lower intensity (but more continuous) periods of burning in savannas. These patterns were consistent with earlier field and modeling work characterizing fire behavior dynamics in different ecosystems. On diurnal timescales, our analysis of the GOES WF_ABBA active fires indicated that fires in savannas, grasslands, and croplands occurred earlier in the day as compared to fires in nearby forests. Comparison with Total Carbon Column Observing Network (TCCON) and Measurements of Pollution in the Troposphere (MOPITT) column CO observations provided evidence that including daily variability in emissions moderately improved atmospheric model simulations, particularly during the fire season and near regions with high levels of biomass burning. The high temporal resolution estimates of fire emissions developed here may ultimately reduce uncertainties related to fire contributions to atmospheric trace gases and aerosols. Important future directions include reconciling top-down and bottom up estimates of fire radiative power and integrating burned area and active fire time series from multiple satellite sensors to improve daily emissions estimates.


Cabergoline is a new long-acting dopamine agonist that is very effective and well tolerated in patients with pathological hyperprolactinemia. The aim of this study was to examine, in a very large number of hyperprolactinemic patients, the ability to normalize PRL levels with cabergoline, to determine the effective dose and tolerance, and to assess the effect on clinical symptoms, tumor shrinkage, and visual field abnormalities. We also evaluated the effects of cabergoline in a large subgroup of patients with bromocriptine intolerance or -resistance. We retrospectively reviewed the files of 455 patients (102 males and 353 females) with pathological hyperprolactinemia treated with cabergoline in 9 Belgian centers. Among these patients, 41% had a microadenoma; 42%, a macroadenoma; 16%, idiopathic hyperprolactinemia; and 1%, an empty sella. The median pretreatment serum PRL level was 124 microg/L (range, 16-26,250 microg/L). A subgroup of 292 patients had previously been treated with bromocriptine, of which 140 showed bromocriptine intolerance and 58 showed bromocriptine resistance. Treatment with cabergoline normalized serum PRL levels in 86% of all patients: in 92% of 244 patients with idiopathic hyperprolactinemia or a microprolactinoma and in 77% of 181 macroadenomas. Pretreatment visual field abnormalities normalized in 70% of patients, and tumor shrinkage was seen in 67% of cases. Side effects were noted in 13% of patients, but only 3.9% discontinued therapy because of side effects. The median dose of cabergoline at the start of therapy was 1.0 mg/week but could be reduced to 0.5 mg/week once control was achieved. Patients with a macroprolactinoma needed a higher median cabergoline dose, compared with those with idiopathic hyperprolactinemia or a microprolactinoma: 1.0 mg/week vs. 0.5 mg/week, although a large overlap existed between these groups. Twenty-seven women treated with cabergoline became pregnant, and 25 delivered a healthy child. One patient had an intended abortion and another a miscarriage. In the patients with bromocriptine intolerance, normalization of PRL was reached in 84% of cases, whereas in the bromocriptine-resistant patients, PRL could be normalized in 70%. We confirmed, in a large-scale retrospective study, the high efficacy and tolerability of cabergoline in the treatment of pathological hyperprolactinemia, leaving few patients with unacceptable side effects or inadequate clinical response. Patients with idiopathic hyperprolactinemia or a microprolactinoma, on average, needed only half the dose of cabergoline as those with macroprolactinomas and have a higher chance of obtaining PRL normalization. Cabergoline also normalized PRL in the majority of patients with known bromocriptine intolerance or -resistance. Once PRL secretion was adequately controlled, the dose of cabergoline could often be significantly decreased, which further reduced costs of therapy.


Since the days of Adam Smith, economists have grappled with a series of familiar problems - but often their ideas are hard to digest, before we even try to apply them to today's issues. Linda Yueh is renowned for her combination of erudition, as an accomplished economist herself, and accessibility, as a leading writer and broadcaster in this field; and in The Great Economists she explains the key thoughts of history's greatest economists, how their lives and times affected their ideas, how our lives have been influenced by their work, and how they could help with the policy challenges that we face today.

In the light of current economic problems, and in particular economic growth, Yueh explores the thoughts of economists from Adam Smith and David Ricardo through Joan Robinson and Milton Friedman to Douglass North and Robert Solow. Along the way she asks, for example: what do the ideas of Karl Marx tell us about the likely future for the Chinese economy? How does the work of John Maynard Keynes, who argued for government spending to create full employment, help us think about state investment? And with globalization in trouble, what can we learn about handling Brexit and Trumpism?

In one accessible volume, this expert new voice provides an overarching guide to the biggest questions of our time.

The Great Economists includes:
Adam Smith
David Ricardo
Karl Marx
Alfred Marshall
Irving Fisher
John Maynard Keynes
Joseph Schumpeter
Friedrich Hayek
Joan Robinson
Milton Friedman
Douglass North
Robert Solow

'Economics students, like others, can learn a lot from this book' - Professor Paul Collier, author of The Bottom Billion

'Not only a great way to learn in an easily readable manner about some of the greatest economic influences of the past, but also a good way to test your own a priori assumptions about some of the big challenges of our time.' - Lord Jim O'Neill, former Chairman at Goldman Sachs Asset Management, former UK Treasury Minister, and author of The Growth Map

'An extremely engaging survey of the lifetimes and ideas of the great thinkers of economic history.' - Professor Kenneth Rogoff, author of The Curse of Cash and co-author of This Time is Different

'This book is a very readable introduction to the lives and thinking of the greats.' - Professor Raghuram Rajan, former Governor of the Reserve Bank of India, and author of I Do What I Do and Fault Lines

'Read it not only to learn about the world's great economists, but also to see how consequential thought innovations can be, and have been.' - Mohamed el-Erian, Chief Economic Adviser at Allianz, former CEO of PIMCO


The Africa Bible Commentary is a unique publishing event-the first one-volume Bible commentary produced in Africa by African theologians to meet the needs of African pastors, students, and lay leaders. Interpreting and applying the Bible in the light of African culture and realities, it furnishes powerful and relevant insights into the biblical text that transcend Africa in their significance. The Africa Bible Commentary gives a section-by-section interpretation that provides a contextual, readable, affordable, and immensely useful guide to the entire Bible. Readers around the world will benefit from and appreciate the commentary's fresh insights and direct style that engage both heart and mind. Key features: * Produced by African biblical scholars, in Africa, for Africa-and for the world * Section-by-section interpretive commentary and application * More than 70 special articles dealing with topics of key importance in to ministry in Africa today, but that have global implications * 70 African contributors from both English- and French-speaking countries * Transcends the African context with insights into the biblical text and the Christian faith for readers worldwide


Bronchopulmonary dysplasia (BPD) remains a major respiratory illness in extremely premature infants. The biological mechanisms leading to BPD are not fully understood, although an arrest in lung development has been implicated. The current study aimed to investigate the occurrence of autophagy in the developing mouse lung and its regulatory role in airway branching and terminal sacculi formation. We found 2 windows of epithelial autophagy activation in the developing mouse lung, both resulting from AMPK activation. Inhibition of AMPK-mediated autophagy led to reduced lung branching in vitro. Conditional deletion of beclin 1 (Becn1) in mouse lung epithelial cells (Becn1Epi-KO), either at early (E10.5) or late (E16.5) gestation, resulted in lethal respiratory distress at birth or shortly after. E10.5 Becn1Epi-KO lungs displayed reduced airway branching and sacculi formation accompanied by impaired vascularization, excessive epithelial cell death, reduced mesenchymal thinning of the interstitial walls, and delayed epithelial maturation. E16.5 Becn1Epi-KO lungs had reduced terminal air sac formation and vascularization and delayed distal epithelial differentiation, a pathology similar to that seen in infants with BPD. Taken together, our findings demonstrate that intrinsic autophagy is an important regulator of lung development and morphogenesis and may contribute to the BPD phenotype when impaired.


The paper sheds light on the change in the concept of obedience within the Society of Jesus since the 1960s. In the aftermath of the Second Vatican Council, a so-called crisis of authority and obedience took place in the Catholic Church and the religious orders. As a consequence, the notions of responsibility and conscience came to the fore in the Jesuit definition of obedience. The religious concept of obedience, that is the obedience towards God, was reassessed as a service to humanity. The paper analyzes how the change in the concept of obedience gave rise to the promotion of social justice, which the Society of Jesus proclaimed at General Congregation 32 in 1974/75. By including the promotion of social justice into their central mission, Jesuits not only fundamentally transformed their self-conception, but also their ethical values. The paper argues that the pursuit of social justice became a form of religious obedience.


This paper reports on recent research into co-operative leadership which aims to support co-operative higher education; where co-operative education is understood as the connection between the co-operative movement and co-operative learning (Breeze 2011). The research was carried out in three co-operatives: a co-operative school, a co-operative university, a workers' co-operative, and an employee owned retail business. The research is framed within a set of catalytic principles established in previous research (Neary and Winn 2016): knowledge, democracy, bureaucracy, livelihood and solidarity. The results have been developed as a diagnostic tool for academics, other staff and students in higher education institutions to assess the extent to which they are already operating in co-operative manner and how these co-operative practices might be further developed. The ultimate aim of these activities is to establish a cooperative university. The research is funded by the Leadership Foundation for Higher Education.


Crista junctions (CJs) are important for mitochondrial organization and function, but the molecular basis of their formation and architecture is obscure. We have identified and characterized a mitochondrial membrane protein in yeast, Fcj1 (formation of CJ protein 1), which is specifically enriched in CJs. Cells lacking Fcj1 lack CJs, exhibit concentric stacks of inner membrane in the mitochondrial matrix, and show increased levels of F1FO–ATP synthase (F1FO) supercomplexes. Overexpression of Fcj1 leads to increased CJ formation, branching of cristae, enlargement of CJ diameter, and reduced levels of F1FO supercomplexes. Impairment of F1FO oligomer formation by deletion of its subunits e/g (Su e/g) causes CJ diameter enlargement and reduction of cristae tip numbers and promotes cristae branching. Fcj1 and Su e/g genetically interact. We propose a model in which the antagonism between Fcj1 and Su e/g locally modulates the F1FO oligomeric state, thereby controlling membrane curvature of cristae to generate CJs and cristae tips.


Upon arterial injury, endothelial denudation leads to platelet activation and delivery of multiple agents (e.g., TXA2, PDGF), promoting VSMC dedifferentiation and proliferation (intimal hyperplasia) during injury repair. The process of resolution of vessel injury repair, and prevention of excessive repair (switching VSMCs back to a differentiated quiescent state), is poorly understood. We now report that internalization of APs by VSMCs promotes resolution of arterial injury by switching on VSMC quiescence. Ex vivo and in vivo studies using lineage tracing reporter mice (PF4-cre × mT/mG) demonstrated uptake of GFP-labeled platelets (mG) by mTomato red–labeled VSMCs (mT) upon arterial wire injury. Genome-wide miRNA sequencing of VSMCs cocultured with APs identified significant increases in platelet-derived miR-223. miR-223 appears to directly target PDGFR&bgr; (in VSMCs), reversing the injury-induced dedifferentiation. Upon arterial injury, platelet miR-223–KO mice exhibited increased intimal hyperplasia, whereas miR-223 mimics reduced intimal hyperplasia. Diabetic mice with reduced expression of miR-223 exhibited enhanced VSMC dedifferentiation and proliferation and increased intimal hyperplasia. Our results suggest that horizontal transfer of platelet-derived miRNAs into VSMCs provides a novel mechanism for regulating VSMC phenotypic switching. Platelets thus play a dual role in vascular injury repair, initiating an immediate repair process and, concurrently, a delayed process to prevent excessive repair.


Abstract. This paper introduces and evaluates the second version of the global aerosol-climate model ECHAM-HAM. Major changes have been brought into the model, including new parameterizations for aerosol nucleation and water uptake, an explicit treatment of secondary organic aerosols, modified emission calculations for sea salt and mineral dust, the coupling of aerosol microphysics to a two-moment stratiform cloud microphysics scheme, and alternative wet scavenging parameterizations. These revisions extend the model's capability to represent details of the aerosol lifecycle and its interaction with climate. Nudged simulations of the year 2000 are carried out to compare the aerosol properties and global distribution in HAM1 and HAM2, and to evaluate them against various observations. Sensitivity experiments are performed to help identify the impact of each individual update in model formulation. Results indicate that from HAM1 to HAM2 there is a marked weakening of aerosol water uptake in the lower troposphere, reducing the total aerosol water burden from 75 Tg to 51 Tg. The main reason is the newly introduced κ-Kohler-theory-based water uptake scheme uses a lower value for the maximum relative humidity cutoff. Particulate organic matter loading in HAM2 is considerably higher in the upper troposphere, because the explicit treatment of secondary organic aerosols allows highly volatile oxidation products of the precursors to be vertically transported to regions of very low temperature and to form aerosols there. Sulfate, black carbon, particulate organic matter and mineral dust in HAM2 have longer lifetimes than in HAM1 because of weaker in-cloud scavenging, which is in turn related to lower autoconversion efficiency in the newly introduced two-moment cloud microphysics scheme. Modification in the sea salt emission scheme causes a significant increase in the ratio (from 1.6 to 7.7) between accumulation mode and coarse mode emission fluxes of aerosol number concentration. This leads to a general increase in the number concentration of smaller particles over the oceans in HAM2, as reflected by the higher Angstrom parameters. Evaluation against observation reveals that in terms of model performance, main improvements in HAM2 include a marked decrease of the systematic negative bias in the absorption aerosol optical depth, as well as smaller biases over the oceans in Angstrom parameter and in the accumulation mode number concentration. The simulated geographical distribution of aerosol optical depth (AOD) is better correlated with the MODIS data, while the surface aerosol mass concentrations are very similar to those in the old version. The total aerosol water content in HAM2 is considerably closer to the multi-model average from Phase I of the AeroCom intercomparison project. Model deficiencies that require further efforts in the future include (i) positive biases in AOD over the ocean, (ii) negative biases in AOD and aerosol mass concentration in high-latitude regions, and (iii) negative biases in particle number concentration, especially that of the Aitken mode, in the lower troposphere in heavily polluted regions.


The therapeutic effects of the blockbuster leukemia drug imatinib may be enhanced when given along with a drug that inhibits a cell process called autophagy, researchers from the Kimmel Cancer Center at Jefferson reported in the Journal of Clinical Investigation. The cell-death effect of imatinib (Gleevec) was potentiated when chloroquine, an autophagy inhibitor, was given with imatinib for the in vitro treatment of chronic myeloid leukemia (CML) cells including the CML stem cells, according to Bruno Calabretta, M.D., Ph.D., professor of Cancer Biology at Jefferson Medical College of Thomas Jefferson University. Autophagy is a process that allows cells to adapt to environmental stresses, and enables drug-treated CML cells to escape cell death. Imatinib is a tyrosine kinase inhibitor that suppresses proliferation and induces death of the malignant cells that cause CML. However, additional effects of the drug have not been studied in detail, according to Dr. Calabretta. In this study, Dr. Calabretta's team, along with Dr. Paolo Salomoni's team from the MRC Toxicology Unit at the University of Leicester in the United Kingdom, found that imatinib induces autophagy in CML stem cells that overexpress a protein called p210BCR/ABL. Stem cells that express this protein have been historically resistant to imatinib and also to second-generation tyrosine kinase inhibitors, including dasatinib, nilotinib and bosutinib. The autophagy process allows stem cells to survive treatment with imatinib, and continue to survive. The researchers used chloroquine to see if it would have an effect on imatinib treatment. The dual treatment with imatinib and chloroquine eliminated most CML stem cells. Also, imatinib-induced cell death was significantly increased in mice inoculated with p210BCR/ABL-expressing cells. "Imatinib's primary effect is inhibiting the proliferation of CML cells, but the frequency of resistance increases in advanced stages of the disease," Dr. Calabretta said. "There is a need to develop new therapeutic approaches that, in combination with tyrosine kinase inhibitors, eliminate CML stem cells that escape imatinib treatment. We show that imatinib induces autophagy, which enables these cells to survive and eventually resume proliferation. We also show that chloroquine, an autophagy inhibitor, combined with imatinib actually appears to potentiate imatinib-induced cell death."