bluuebunny/crossref_metadata_2025 huggingface dataset:
The “Good Doctor”
Authors: Boudreau J. Donald , Cassell Eric J. , Fuks Abraham
Published: March 2018

This chapter explores the commonly expressed phrase the good doctor from the perspectives of the lay public, patients, and physicians. It examines the various personal qualities or attributes commonly considered desirable for optimal doctoring. The perspectives from these various sources are combined so as to arrive at a unified and coherent understanding of the “good” doctor; it includes notions of humanism; a set of ethical principles, duties, or responsibilities; and lists of desirable personal traits. The notion of the “good enough” doctor is also broached. The chapter concludes by considering the meaning of professionalism and its overlap with ideal doctoring skills.
Competency-Based Education
Authors: Boudreau J. Donald , Cassell Eric J. , Fuks Abraham
Published: March 2018

The historical roots of competency-based approaches to education are presented. The word competency and its cognates competence, competent, and competencies are defined. The conditions that have permitted the competency-based movement to become entrenched in many national and pan-national institutions are discussed. There is an overwhelming perception by opinion leaders that learners are currently not subject to sufficiently valid and robust assessments of clinical performance. Competency-based approaches are considered promising as they provide protocols for frequent assessments. Clinical teachers sometimes visualize these assessment strategies as providing “educational biopsies” of learners’ skills and so-called competencies. Design considerations in competency-based approaches, namely, the concepts of entrustability, graded levels of proficiency, and performance milestones, are discussed. The chapter ends with opinions on the theoretical advantages and disadvantages of this approach.
Prelude
Authors: Miksza Peter , Elpus Kenneth
Published: March 2018

This chapter describes the goals and general approach of this book. The general purposes of the chapters contained in Parts I and II are presented. A brief statement about how quantitative research can feel foreign to those coming from a classroom setting and suggestions for expanding one’s sense of identity is provided. A basic orientation to quantitative research design and analysis is provided. A brief commentary on data, variables, and quantitative analysis is provided as a prelude to the materials that follow in the rest of the book. Statistical methods are put forward as tools that can be used to discover patterns and trends within the complexities of music teaching and learning phenomena.
Characteristics of Scientific Inquiry
Authors: Miksza Peter , Elpus Kenneth
Published: March 2018

This chapter introduces the reader to basic characteristics of science and situates the design and analysis considerations presented throughout the book within the context of scientific inquiry. A brief description of key historical developments regarding the philosophy of science is provided. An overview of the fundamental aspects of inductive and deductive scientific reasoning and the importance of falsification to scientific progress is presented. In addition, the values of objectivity and transparency as well as the importance of scientific community are stressed. The usefulness of statistical tools for helping researchers clarify their questions, establish criteria for their judgments, and communicate evidence for their claims is also discussed.
Correlational Design and Analysis
Authors: Miksza Peter , Elpus Kenneth
Published: March 2018

Interests in how variables may relate to each other and how systems of relationships among variables may be at play often underlie the questions music education researchers pose. This chapter describes basic design and analysis considerations in research that involves the systematic investigation of whether and how variables are related; in other words, correlational research. The chapter poses correlational research as an extension of the book’s previous discussion of descriptive research. The chapter briefly describes the role of correlational studies in advancing theory, presents several issues to consider when designing studies, and provides an introduction to correlation as a statistical concept.
Regression
Authors: Miksza Peter , Elpus Kenneth
Published: March 2018

This chapter presents the logic and technique of analyzing data using simple linear regression and multiple linear regression. Regression is a remarkably versatile statistical procedure that can be used not only to understand whether or not variables are related to each other (as in correlation) but also for providing estimates of the direction of the relationship and of the degree to which the variables are related. Beginning with a simple bivariate case analyzing a single predictor on a single outcome, the flexibility and ability for regression to analyze increasingly complex data, including binary outcomes, is discussed. Particular attention is paid to the ability of regression to be used to estimate the effect of a predictor on an outcome while statistically “controlling” for the values of other observed variables.
Early Life and Career of Master Tara Singh
Authors: Grewal J.S.
Published: March 2018

In the early 1890s, Master Tara Singh (Nanak Chand) was so impressed by the stories of Singh martyrs that he thought of becoming a Keshdhārī Singh. Initiated by Sant Attar Singh in 1901, Master Tara Singh decided to dedicate his life to the service of the Sikh Panth. After the government took over the management of Khalsa College, Amritsar, he began to participate in all anti-government agitations. As Head Master of Khalsa High School, Lyallpur, he was closely associated with the group of Sikh leaders who were more radical than the Chief Khalsa Diwan. His sympathy with the ‘Canadian’ Sikhs, and his interest in the Komagata Maru voyage and the Budge Budge firing made him all the more anti-British. His familiarity with gurbāṇī, Sikh history, and Punjabi literature was reflected in his controversy with the Arya Samaj leaders.
Master Tara Singh in the Akali Movement
Authors: Grewal J.S.
Published: March 2018

The newspaper Akali, started by the radical Sikh leaders in June 1920, articulated their concern for the liberation of Khalsa College, Amritsar, the historic gurdwaras, and eventually the whole country. On the announcement of direct action by the Akali volunteers to reconstruct the demolished wall of Gurdwara Rakabganj, it was quickly rebuilt by the government. The Punjab bureaucracy relinquished its control over the Khalsa College in favour of the moderate leaders of the Chief Khalsa Diwan. For the control of Darbar Sahib at Amritsar and other gurdwaras, the Shiromani Gurdwara Prabandhak Committee (SGPC) was formed in November 1920 and the Shiromani Akali Dal was formed in December. The non-violent morchās launched by the SGPC in 1922–3 were eminently successful. Master Tara Singh emerged as one of the prominent Akali leaders and the best ideologue of the Akali Movement.
In Search of Political Autonomy
Authors: Grewal J.S.
Published: March 2018

In August 1940, Master Tara Singh started negotiations with the Congress leaders about whether or not to support the government in its war efforts. Mahatma Gandhi’s response obliged him eventually to resign from the Congress Working Committee. Master Tara Singh supported the programme of the Khalsa Defence of India League formed early in 1941 under the leadership of Maharaja Yadvindra Singh of Patiala. In March 1942, Stafford Cripps brought a proposal that appeared to concede Pakistan. His mission failed but Master Tara Singh remained seriously perturbed over the possibility of the Sikhs being placed under perpetual Muslim domination. The Sikander–Baldev Singh Pact enabled Baldev Singh, a non-Akali legislator, to replace Dasaundha Singh as the Sikh minister in the Unionist ministry. Thus, Master Tara Singh’s idea was to strengthen the Sikh position without infringing his formal understanding with the Congress.
Seventy-Five Days to Partition
Authors: Grewal J.S.
Published: March 2018

Master Tara Singh issued a statement on 4 June that the 3 June Plan did not give ‘any power or status’ to the Sikhs or anything ‘safeguarding their position or interests’. The ultimate acceptance of the plan, he said, would depend on the terms of reference for the Boundary Commission. A cycle of retaliation and reprisal started before 15 August 1947 as a prelude to an unprecedented exodus in world history. Giani Kartar Singh was thinking of reorganization of the East Punjab to form ‘a Sikh majority province’, including the princely states of the plains. But Nehru was opposed to any kind of political safeguards. His vision of India after Independence had little room for the long-cherished hopes and aspirations of the Akalis.
Making of the New Constitution
Authors: Grewal J.S.
Published: March 2018

Of special interest to the Sikhs in the making of a new constitution were political safeguards, the issues of language, and linguistic states. In 1947 it was decided to have proportionate reservations for minorities. However, the question of safeguards for the Sikhs was postponed. A sub-committee formed in February 1948 saw no reason to make an exception in their case. In May 1949, Sardar Patel reopened the question of reservations but decided to have no reservations for any religious minority. On the issue of the official language for India, the final decision was in favour of Hindi in Devnagri script. On the issue of linguistic states, the Constituent Assembly reluctantly formed a commission which recommended that there was no need of creating linguistic states. The Constitution adopted in 1950, thus, did not satisfy any of the political aspirations of the Sikhs as a community.
Failure of the Compromise
Authors: Grewal J.S.
Published: March 2018

On the basis of the Regional Formula, Pepsu was merged with the Punjab and the new state was inaugurated on 1 November 1956. The other provisions of the Regional Formula were diluted or indefinitely delayed. Apart from the ‘Save Hindi’ agitation, Master Tara Singh differed widely with Nehru on three major issues. The first related to their understanding about the number of seats to be given to the Akali candidates. The second issue was the defection of Gian Singh Rarewala to join the Congress before the decision of the Akali Dal in favour of merger. The third issue was Nehru’s all-out support to Partap Singh Kairon despite serious charges of misuse of office. By October 1958, the Regional Formula was dead so far as Master Tara Singh was concerned.
Master Tara Singh Loses Ground
Authors: Grewal J.S.
Published: March 2018

After the failure of the Punjabi Suba agitation in 1960–1, Master Tara Singh began to lose ground in Akali politics. Sant Fateh Singh attributed this failure to him, and declared that his own conception of the Akali demand was fundamentally different from that of Master Tara Singh. Throughout 1963 the Sant conducted a systematic campaign against Master Tara Singh, underlining his weakness as a leader and highlighting his own commitment to the cause of the Sikh Panth. He claimed to represent the majority of the Akalis. The success of his nominee in the election for Presidentship of the SGPC in June 1964 confirmed his claim. It appeared before the end of the year that Master Tara Singh would never recover the lost ground. Early in 1965 he left the field free for Sant Fateh Singh and went to some unknown place.
The ‘Infiltrators’ of Delhi
Authors: Shamshad Rizwana
Published: March 2018

The presence of Bangladeshi migrants in Delhi, and in India itself, became a major element in the election campaigns of Hindu nationalists in the 1990s. For Hindu nationalists, the Hindu Bangladeshis in India are ‘refugees’ and the Muslim Bangladeshis are ‘infiltrators’ who are actively conspiring against the Hindus of India. This chapter investigates the context and timing for the inclusion of Bangladeshi migrants by the Sangh Parivar into their Hindutva agenda. The interviews in Delhi with the influential leaders from the BJP, Congress, RSS, and VHP and notable civil society members provide an insight into the local state-level discourses, and also into the nationwide controversies concerning Bangladeshi migrants in India.
Conclusion
Authors: Shamshad Rizwana
Published: March 2018

The concluding chapter discusses the current state of nationalist thoughts in three Indian states: Assam, West Bengal, and Delhi based on the findings that derived from interviews with the key political parties and civil society members in these three states. The chapter then analyses the nationalist thoughts against the backdrop of the theoretical framework and grand theories of nationalism that were discussed in the first chapter. Further, it provides an analysis of the cross-regional nature of the nationalist debate on Bangladeshi migrants present in these three states. Finally, it discusses the current state of nationalism in India.
His Life Is His Message
Authors: Rao Koneru Ramakrishna
Published: March 2018

This chapter is a thematic sketch of Gandhi’s life and the lessons we may learn from it. The chapter discusses his early life and his experiences in South Africa which had a profound transformative effect on him, and how subsequently he was pulled into the vortex of Indian politics and the freedom movement. While describing the life experience of Gandhi, the chapter brings into focus a number of key Gandhian concepts like satyagraha that underlie Gandhi’s philosophy and practices. More important is our attempt to make Gandhi’s life relevant to readers and to show how the Mahatma’s life is a splendid blend of thought and action.
Conclusion
Authors: Sharma Mukul
Published: March 2018

In the conclusion the author summarizes his arguments and research findings, bringing in discussions on some of the initiatives taken by the Dalits and other organizations to link up the issues of caste, nature, and Dalit movements. He points towards the new generation of environmental questions, especially in the context of caste, Dalits, identity, ethnicity, minority, democracy, and development. Dalit–Brahmin encounters in the realm of nature have been antagonistic, but there could be some internal commonalities dissolving the differences and complementing each other at complex levels. He concludes that the linkages between nature and caste, ecology and Dalits, are dynamic, and can offer much in academic research, in the fields of both Dalit and environmental studies. A study of the interplay between them can enrich both arenas providing new visions and insights. Traditional environmentalism and environmental politics have built the bedrock of their politics on community and nation. It is not likely that their concerns will be altered altogether. However, the new generation of environmental activism and writings have begun to pay more attention to hitherto unseen people and unheard voices, with conflicting positions.
Albert Howard and the World as Shropshire
Authors: Barton Gregory A.
Published: March 2018

Albert Howard spent his boyhood in Shropshire county, England. He was educated at Wellington College, the Royal College of Science in South Kensington, London, and St. John’s College, Cambridge, studying under Marshal Ward. He took his first job teaching at Harrison College, Barbados, and then served as Mycologist and Agricultural Lecturer at the Imperial Department of Agriculture for the West Indies. Returning to England, he took a position at Wye College experimenting with hops. This chapter looks in more depth at the early life of Albert Howard and traces the influence that this period has upon his later ideas. In addition, the family background of Gabrielle and Louise Mattaei is also described in depth.
The Howards in India
Authors: Barton Gregory A.
Published: March 2018

Lord Curzon, Viceroy of India, established the Imperial Research Agricultural Institute to draw scientists together in a single location to solve the challenges facing India’s farmers, which included plant disease, soil infertility, low production per acre, and famine. Unknown to most organic farming enthusiasts is the fact that Howard supported the use of artificial pesticides for fruits and vegetables imported into India, and that his colleagues at Pusa pioneered and published many of the same principles as the famous “Indore compost” method that Howard popularized in his book Agricultural Testament, upon his retirement from India in 1939. Howard took these experiments further than his colleagues, formulated them, and popularized them.
The Search for Pre-Modern Wisdom
Authors: Barton Gregory A.
Published: March 2018

Over time, the myth of the peasant origins of the organic farming movement has come to prominence amongst those who advocate organic farming methods, with the belief being that, through his writings on organic farming, Howard had bequeathed to the West the ancient wisdom of the East. This chapter traces the origins of the organic farming protocols to Albert Howard, rather than pre-industrial peasant agriculture among the Hunza. It highlights that the Indore Methods of composting solved a practical need to raise soil fertility without the cost of chemical fertilizers, and draws attention to the unique accomplishments of Albert and Gabrielle Howard at Indore.
The Black Book of Quantum Chromodynamics
Authors: Campbell John , Huston Joey , Krauss Frank
Published: March 2018

The LHC (Large Hadron Collider) will serve as the energy frontier for high-energy physics for the next 20 years. The highlight of the LHC running so far has been the discovery of the Higgs boson, but the LHC programme has also consisted of the measurement of a myriad of other Standard Model processes, as well as searches for Beyond-the-Standard-Model physics, and the discrimination between possible new physics signatures and their Standard Model backgrounds. Essentially all of the physics processes at the LHC depend on quantum chromodynamics, or QCD, in the production, or in the decay stages, or in both. This book has been written as an advanced primer for physics at the LHC, providing a pedagogical guide for the calculation of QCD and Standard Model predictions, using state-of-the-art theoretical frameworks. The predictions are compared to both the legacy data from the Tevatron, as well as the data obtained thus far from the LHC, with intuitive connections between data and theory supplied where possible. The book is written at a level suitable for advanced graduate students, and thus could be used in a graduate course, but is also intended for every physicist interested in physics at the LHC.
Hard Scattering Formalism
Authors: Campbell John , Huston Joey , Krauss Frank
Published: March 2018

The hard scattering formalism is introduced, starting from a physical picture based on the idea of equivalent quanta borrowed from QED, and the notion of characteristic times. Contact to the standard QCD treatment is made after discussing the running coupling and the Altarelli–Parisi equations for the evolution of parton distribution functions, both for QED and QCD. This allows a development of a space-time picture for hard interactions in hadron collisions, integrating hard production cross sections, initial and final state radiation, hadronization, and multiple parton scattering. The production of a W boson at leading and next-to leading order in QCD is used to exemplify characteristic features of fixed-order perturbation theory, and the results are used for some first phenomenological considerations. After that, the analytic resummation of the W boson transverse momentum is introduced, giving rise to the notion of a Sudakov form factor. The probabilistic interpretation of the Sudakov form factor is used to discuss patterns in jet production in electron-positron annihilation.
QCD at Fixed Order: Technology
Authors: Campbell John , Huston Joey , Krauss Frank
Published: March 2018

This chapter is devoted to the technology of fixed-order calculations, in particular, in QCD. After a short summary of methods for the efficient evaluation of tree-level scattering amplitudes for multi-particle production, and their integration in phase space, next-to leading order corrections in QCD are addressed. Techniques for the evaluation of loop amplitudes with modern methods, based on the reduction to master integrals, either analytically or with numerical unitarity cut methods, are discussed in some detail. After identifying the problem of infrared divergences and illuminating their treatment with a toy model, Catani-Seymour subtraction is explicitly introduced and exemplified for two cases, namely inclusive hadron production in electron-positron annihilation and inclusive W boson production in hadron collisions. This chapter concludes with some remarks concerning the rapidly developing field of next-to-next-to leading order calculations.
QCD at Fixed Order: Processes
Authors: Campbell John , Huston Joey , Krauss Frank
Published: March 2018

At the core of any theoretical description of hadron collider physics is a fixed-order perturbative treatment of a hard scattering process. This chapter is devoted to a survey of fixed-order predictions for a wide range of Standard Model processes. These range from high cross-section processes such as jet production to much more elusive reactions, such as the production of Higgs bosons. Process by process, these sections illustrate how the techniques developed in Chapter 3 are applied to more complex final states and provide a summary of the fixed-order state-of-the-art. In each case, key theoretical predictions and ideas are identified that will be the subject of a detailed comparison with data in Chapters 8 and 9.
Introduction
Authors: Lee Alexander
Published: March 2018

Although the humanists greeted the revival of imperial aspirations in Northern Italy with unvarnished enthusiasm, their conception of Empire has been treated rather dismissively in scholarly literature. In most surveys of political thought, it has simply been ignored. But even where it has been acknowledged, it has been portrayed either as a digression from a dominant discourse of communal liberty, or as a flight of nostalgic whimsy divorced from the ‘real’ spirit of humanism. Challenging the assumptions on which such attitudes have been based, this chapter demonstrates that the political life of the regnum Italicum cannot be described solely in terms of the conflict between communes and signori; that the ideal of liberty was not tied to any one form of government; and that there was no ‘natural’ connection between humanism and republicanism. In doing so, it provides the rationale for, and the methodology employed in, this study.
History, Providence, and Empire
Authors: Lee Alexander
Published: March 2018

A few years after the humanist dream of a revivified Empire had put down roots in Padua, a parallel strain of imperialist thought was germinating in Verona. There in the shadow of the cathedral library, a small group of like-minded figures were attempting to revive classical culture more through the study of history and philology than through stylistic imitation. Like their Paduan contemporaries, they were deeply troubled by the condition of their times, and lamented the emergence of factionalism and tyranny. They, too, longed for peace and liberty, and saw the Empire as their best hope. But as this chapter shows, they were more concerned with the fate of humanity as a whole than with that of a single city; and rather than relying on the letter of feudal law, they instead founded their imperialism on a deep appreciation for the Roman past and the Church Fathers.
Imperium and Sacerdotium
Authors: Lee Alexander
Published: March 2018

For many years, humanist attitudes towards the relationship between papacy and Empire have tended to be viewed in terms of the rivalry between the Guelfs and the Ghibellines. As this chapter argues, however, such a heuristic approach is anything but helpful. Indeed, it actually distorts our understanding of humanist thought. Rather than being constrained by narrow factional designations, the humanists nurtured a resolutely dualistic vision of imperium and sacerdotium throughout the fourteenth century. Carefully following the course of the conflict between Empire and papacy, they sought to refute papal claims to plenitude of power, while still upholding the emperor’s obligation to defend the Church from her enemies, and even to resolve schisms. Yet though they were not averse to pouring scorn upon successive popes—both contemporary and historical—this chapter will show that they were also prepared to criticize emperors whenever they felt the separation of powers was being violated.
The “Unmixing” of Lands
Authors: Smith Leonard V.
Published: March 2018

Chapters 3 and 4 draw in an ironic way from Lord Curzon’s phrase of peacemaking in the twentieth century as comprising the “unmixing of peoples.” Both chapters consider territoriality as a political practice of “unmixing” both lands and peoples. The term “unmixing” actually meant imposing rigid categorizations of ethnicity with considerable political consequences. British, French, and American schools of political geography provided the intellectual infrastructure. The council of Great Powers in its various forms established itself as a sovereign court in Paris that heard and adjudicated claims from nationalists in the successor states. In some cases, such as Czechoslovakia, the Council found discourses rooted in “history” and “ethnicity” decisive. In the case of Hungary, defeat meant that the Council would resolve doubt by siding with rival successor states. In some cases, notably some of the borders of Germany and Poland and in the mandates, no school of political geography could master the challenges of “unmixing” lands.
The “Unmixing” of Peoples
Authors: Smith Leonard V.
Published: March 2018

The Paris Peace turned to population policies when and where it could not draw boundaries to suit peoples. Plebiscites, ostensibly the most democratic of population policies, took place in the context of choices already having been made as to the territories in which plebiscites would be held, and who could vote in them. Treaties for minority protection sought to guarantee ethnic or religious difference within the ethno-national state. Successor states bitterly contested them as an infringement of state sovereignty. The racial categorization of the mandates constituted a territorial policy transformed into a population policy. Peoples were classified according to how avidly the mandatory power sought direct annexation of the territory in question. “Population exchanges” simply carried a certain version of “national self-determination” to one logical conclusion. With the tacit approval of the conference, peoples were categorized and forcibly relocated for reasons of state.
An Evolutionary Process—The Federalization of Corporate Governance
Authors: Steinberg Marc I.
Published: March 2018

This chapter provides an overview regarding the federalization of corporate governance as an evolutionary process. From this perspective, the chapter examines both state and federal law that impact corporate governance. As the chapter explains, from a historical perspective, the states emerged as the primary regulator of corporate governance. Today, Delaware has emerged as the preeminent state where publicly-held corporations elect to incorporate. Nonetheless, federal law, even from a traditional perspective, impacted corporate governance, such as the SEC’s shareholder proposal rule adopted over 75 years ago. With the enactment of the Sarbanes-Oxley Act of 2002, the Dodd-Frank Act of 2010, SEC rules adopted under the authority of these statutes, and the emergence of stricter substantive listing requirements mandated by the national stock exchanges, federal law principles are now firmly established.
The Experimental Conception Hospital: Dating Pregnancy and the Gothic Imagination
Authors: Davis Isabel
Published: March 2018

The Experimental Conception Hospital is a fictional laboratory described in a note by Robert Lyall on the medical evidence given in the Gardner Peerage dispute (1825–26). This fantasy institution would discover the natural length of human gestation and ascertain from when and what to date conception, calculations which eluded the House of Lords Peerage Committee which heard the case. This article introduces the Gardner case and Lyall’s writing about it, focusing on the Gothicism which emerges particularly in relation to the perceived secrecy of the female reproductive body. By considering Lyall’s Experimental Conception Hospital alongside three other technologies—the Panopticon, the hot air balloon and anatomical drawings of the gravid uterus—this article discovers the anachronistic persistence of supposedly out-dated modes of thoughts around female sexuality and reproductive biology in an apparently hyper-modern moment.
Folate intake, serum folate, and risk of esophageal cancer: a systematic review and dose–response meta-analysis
Authors: Ni Yingchun , Du Jinge , Yin Xiaolin , Lu Ming
Published: March 2018

The dose–response relationship between folate and the risk of esophageal cancer (EC) is not clear. To further elucidate their relationships, we carried out a dose–response meta-analysis of folate intake, serum folate, and the risk of EC. PubMed, Embase, Web of Science, and China National Knowledge Infrastructure were searched for observational studies until September 2016. Then, we carried out a systematic review and dose–response meta-analysis using Stata 14.0 software. Subgroup analyses were further carried out according to study characteristics and adjustment confounders. A total of 23 studies with a total of 3886 patients were enrolled in this study. The pooled odds ratios for EC in the highest versus the lowest levels of folate intake and serum folate were 0.64 (0.54–0.76, P<0.001) and 0.45 (0.19–1.07, P=0.071), respectively. Dose–response meta-analyses were carried out to assess associations between folate intake, serum folate, and EC risk. When serum folate is 10 μg/l higher than the lowest reference dosage (3.44 μg/l), EC decreased risk with an increase in serum folate levels. When folate intake is 50 μg/day higher than the lowest reference dosage (125.21 μg/day), the EC risk is decreased with an increase in folate intake. Finally, the results support that folate can promote public health through decreasing EC risk in a certain dosage range; otherwise, the protective effects might be reduced.
Xanthomatous Cells in Cutaneous Graft-Versus-Host Disease Biopsies: A Clue for the Diagnosis of Hepatic Graft-Versus-Host Disease
Authors: Gamé Denise , López Lucia , Román Concepción , Santos-Briz Ángel
Published: March 2018

Graft-versus-host disease (GVHD) is one of the most common and serious complications of hematopoietic stem-cell transplantation that mainly affects the skin, gastrointestinal tract, and liver. Hepatic GVHD is associated with high morbidity and mortality, and its diagnosis can be especially challenging because of nonspecific clinical signs and symptoms. It must be suspected in patients with elevated liver enzymes and cholestasis, especially in those with a history of preceding skin rash and diarrhea. We describe 3 patients with cutaneous and hepatic GVHD that presented with severe hypercholesterolemia and hypertriglyceridemia, and no xanthomatous macular lesions, in which cutaneous biopsies revealed the presence of xanthomatous dermal histiocytes. We propose that the presence of these xanthomatous cells in skin biopsies from patients with cutaneous GVHD could be a dermatopathological clue for the diagnosis of hepatic GVHD.
Cholesterol Clefts in Basal Cell Carcinoma: An Under-Recognized Association
Authors: Kim Hee Joo , Park Se Ha , Lee Seul Ki , Kim Jeong Soo , Baek Jinok , Park Hyang Joon , Roh Joo Young
Published: March 2018

Cholesterol clefts have rarely been described in cutaneous tumors other than lipid-rich tumors. However, they seem to be a relatively common phenomenon in basal cell carcinoma (BCC). This study was undertaken to determine the frequency of cholesterol cleft deposition in BCCs, and to identify associated histopathologic and clinical features. Twenty-eight of 249 BCC cases reviewed showed features of cholesterol cleft. Mean disease duration in those with cholesterol cleft was significantly longer than in those without cholesterol cleft (5.58 vs. 3.29 years, respectively; P = 0.013). Sex and age distributions, and average tumor longest diameter (11.6 vs. 9.41 mm) were no different for those with or without cholesterol clefts. The most common anatomical location was the nose in both those with and without cholesterol clefts. BCCs without cholesterol clefts more frequently involved the periauricular and perioral areas, and areas other than the head and neck, such as the trunk and lower extremities (P = 0.087). Histopathologic features of necrosis (26/28, 92.86%), keratinization (19/28, 67.86%), and pigment deposition (18/28, 64.29%) were found to be associated with cholesterol clefts. Cholesterol clefts were intratumorally located in 27/28 cases (96.43%), and stromally located in 2 cases (7.14%); intravascularly located cholesterol clefts were observed in no case. In conclusion, this study shows that cholesterol clefts are relatively common in BCC, and suggests that cholesterol crystal deposition could be associated with longer disease duration and microtrauma.
Multifocal Skin Tuberculosis
Authors: Malaventura Cristina , Bulian Anna , Cacciatore Euro , Fiumana Elisa , Govoni Maria Rita , Maggiore Giuseppe , Borgna-Pignatti Caterina
Published: March 2018

Tuberculosis (TB) is a severe problem in underdeveloped countries. Cutaneous TB is rare and often goes unrecognized. We report a Pakistani child with multifocal cutaneous and pulmonary TB. Microbiologic diagnosis was obtained when the abscesses were biopsied. Four-drug therapy produced rapid improvement of the lesions. A high level of suspicion must be maintained when evaluating children from countries at risk.
Individual differences in response precision correlate with adaptation bias
Authors: Mattar Marcelo G. , Carter Marie V. , Zebrowitz Marc S. , Thompson-Schill Sharon L. , Aguirre Geoffrey K.
Published: March 2018

The internal representation of stimuli is imperfect and subject to bias. Noise introduced at initial encoding and during maintenance degrades the precision of representation. Stimulus estimation is also biased away from recently encountered stimuli, a phenomenon known as adaptation. Within a Bayesian framework, greater biases are predicted to result from poor precision. We tested for this effect in individual difference measures. 202 subjects contributed data through an on-line experiment (https://cfn.upenn.edu/iadapt). During separate face and color blocks, subjects performed three different tasks: an immediate stimulus-match (15 trials), a 5 seconds delayed match (30 trials), and 5 seconds of adaptation followed by a delayed match (30 trials). The stimulus spaces were circular and subjects entered their responses using a color/face wheel. Bias and precision of responses were extracted by fitting a mixture of von Mises distributions to account for random guesses. Two blocks of each measure were obtained, allowing for tests of measure reliability. We found that reliable differences between individuals in precision were as great as those between tasks or materials. The adaptation manipulation induced the expected bias in responses (colors: 7.8°; faces: 5.0°), and the magnitude of this bias reliably and substantially varied between subjects. Across subjects, there was a negative correlation between mean precision and bias (color: ρ = −0.26; faces: ρ = −0.13). This relationship was replicated in a new experiment with 192 subjects (color: ρ = −0.22; faces: ρ = −0.19). This result is consistent with a Bayesian observer model, in which individual differences in the precision of perceptual representation influences the magnitude of adaptation bias.
Perturbed functional networks in Alzheimer’s Disease reveal opposing roles for TGIF and EGR3
Authors: Canchi Saranya , Raao Balaji , Masliah Deborah , Rosenthal Sara Brin , Sasik Roman , Fisch Kathleen M. , Jager Philip De , Bennett David A. , Rissman Robert A.
Published: March 2018

While Alzheimer’s disease (AD) is the most prevalent cause of dementia, complex combinations of the underlying pathologies have led to evolved concepts in clinical and neuropathological criteria in the past decade. Pathological AD can be decomposed into subsets of individuals with significantly different antemortem cognitive decline rates. Using transcriptome as a proxy for functional state, we preselected 414 expression profiles of clinically and neuropathologically confirmed AD subjects and age matched non-demented controls sampled from a large community based neuropathological study. By combining brain tissue specific protein interactome with gene network, we identify functionally distinct composite clusters of genes which reveal extensive changes in expression levels in AD. The average global expression for clusters corresponding to synaptic transmission, metabolism, cell cycle, survival and immune response were downregulated while the upregulated cluster had a large set of uncharacterized pathways and processes that may constitute an AD specific phenotypic signature. We identified four master regulators across all clusters of differentially expressed genes by enrichment analysis includingTGIF1andEGR3.These transcription factors have previously not been associated with AD and were validated in brain tissue samples from an independent AD cohort. We identifyTGIF1,a transcriptional repressor as being neuroprotective in AD by activating co-repressors regulating genes critical for DNA repair, maintaining homeostasis and arresting cell cycle. In addition, we show that loss ofEGR3regulation, mediates synaptic deficits by targeting the synaptic vesicle cycle. Collectively, our results highlight the utility of integrating protein interactions with gene perturbations to generate a comprehensive framework for characterizing the alterations in molecular network as applied to AD.
Transcription-dependent regulation of replication dynamics modulates genome stability
Authors: Blin Marion , Le Tallec Benoît , Naehse Viola , Schmidt Mélanie , Millot Gael A. , Prioleau Marie-Noëlle , Debatisse Michelle
Published: March 2018

Replication stress is a primary threat to genome stability and has been implicated in tumorigenesis1, 2. Common fragile sites (CFSs) are loci hypersensitive to replication stress3 and are hotspots for chromosomal rearrangements in cancers4. CFSs replicate late in S-phase3, are cell-type dependent4–6 and nest within very large genes4, 7–9. The mechanisms responsible for CFS instability are still discussed, notably the relative impact of transcription-replication conflicts7, 8, 10versus their low density in replication initiation events5, 6. Here we address the relationships between transcription, replication, gene size and instability by manipulating the transcription of three endogenous large genes, two in chicken and one in human cells. Remarkably, moderate transcription destabilises large genes whereas high transcription levels alleviate their instability. Replication dynamics analyses showed that transcription quantitatively shapes the replication program of large genes, setting both their initiation profile and their replication timing as well as regulating internal fork velocity. Noticeably, high transcription levels advance the replication time of large genes from late to mid S-phase, which most likely gives cells more time to complete replication before mitotic entry. Transcription can therefore contribute to maintaining the integrity of some difficult-to-replicate loci, challenging the dominant view that it is exclusively a threat to genome stability.
How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
Authors: Chao Luke H. , Jang Jaebong , Johnson Adam , Nguyen Anthony , Gray Nathanael S. , Yang Priscilla L. , Harrison Stephen C.
Published: March 2018

Dengue virus (DV) is a compact, icoshedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic “fusion loops”. We previously characterized the steps in membrane fusion for the related West Nile virus (WNV), using recombinant, WNV virus-like particles (VLPs) for single-particle experiments. Trimerization and membrane engagement are rate-limiting; fusion requires at least two adjacent trimers; availability of competent monomers within the contact zone between virus and target membrane creates a trimerization bottleneck. We have extended that work to dengue VLPs, from all four DV serotypes, finding an essentially similar mechanism. Small-molecule inhibitors of DV infection that target E block its fusion-inducing conformation change. We show that ∼15 bound molecules per particle (∼8.5 % occupancy) completely prevent fusion, in accord with the proposed mechanism and the likely inhibitor binding site on E.

Impact statement

Single-particle studies of dengue-virus membrane fusion and the effect of small-molecule inhibitors of infection clarify the viral fusion mechanism.
Developmental genetics in a complex adaptive structure, the weevil rostrum
Authors: Davis S.R.
Published: March 2018

The rostrum of weevils (Curculionidae) is a novel, complex, adaptive structure that has enabled this huge beetle radiation to feed on and oviposit in a wide spectrum of plant hosts, correlated with diverse life histories and tremendous disparity in rostrum forms. In order to understand the development and evolution of this structure, transcriptomes were produced inde novoassemblies from the developing pre-pupal head tissues of two distantly related curculionids, the rice weevil (Sitophilus oryzae) and the mountain pine beetle (Dendroctonus ponderosae), which have highly divergent rostra. While there are challenges in assessing differences among transcriptomes and in relative gene expression from divergent taxa, tests for differential expression patterns of transcripts yielded lists of candidate genes to examine in future work. RNA interference was performed withS. oryzaefor functional insight into the Hox geneSex combs reduced. Scrhas a conserved function in labial and prothoracic identities, but it also demonstrates a novel role in reduction of ventral head structures, namely the gula, submentum, and associated sulci, in weevils. Ultimately, this study makes strides towards elucidating how the weevil rostrum initially formed and the profound phenotypic diversity it has acquired throughout the curculionoid lineages. It furthermore initiates a better understanding of the genetic framework that permitted the diversification of such an immense lineage as the weevils.

Summary statement

This study begins exploring the development of a novel, complex structure in one of the largest families of organisms, the weevils.
Engineering targeted deletions in the mitochondrial genome
Authors: Campbell Jarryd M. , Perales-Clemente Ester , Ata Hirotaka , Vidal-Folch Noemi , Liu Weibin , Clark Karl J. , Xu Xiaolei , Oglesbee Devin , Nelson Timothy J. , Ekker Stephen C.
Published: March 2018

Summary Paragraph

Mitochondria are a network of critical intracellular organelles with diverse functions ranging from energy production to cell signaling. The mitochondrial genome (mtDNA) consists of 37 genes that support oxidative phosphorylation and are prone to dysfunction that can lead to currently untreatable diseases. Further characterization of mtDNA gene function and creation of more accurate models of human disease will require the ability to engineer precise genomic sequence modifications. To date, mtDNA has been inaccessible to direct modification using traditional genome engineering tools due to unique DNA repair contexts in mitochondria1. Here, we report a new DNA modification process using sequence-specific transcription activator-like effector (TALE) proteins to manipulate mtDNA in vivo and in vitro for reverse genetics applications. First, we show mtDNA deletions can be induced in Danio rerio (zebrafish) using site-directed mitoTALE-nickases (mito-nickases). Using this approach, the protein-encoding mtDNA gene nd4 was deleted in injected zebrafish embryos. Furthermore, this DNA engineering system recreated a large deletion spanning from nd5 to atp8, which is commonly found in human diseases like Kearns-Sayre syndrome (KSS) and Pearson syndrome. Enrichment of mtDNA-deleted genomes was achieved using targeted mitoTALE-nucleases (mitoTALENs) by co-delivering both mito-nickases and mitoTALENs into zebrafish embryos. This combined approach yielded deletions in over 90% of injected animals, which were maintained through adulthood in various tissues. Subsequently, we confirmed that large, targeted deletions could be induced with this approach in human cells. In addition, we show that, when provided with a single nick on the mtDNA light strand, the binding of a terminal TALE protein alone at the intended recombination site is sufficient for deletion induction. This “block and nick” approach yielded engineered mitochondrial molecules with single nucleotide precision using two different targeted deletion sites. This precise seeding method to engineer mtDNA variants is a critical step for the exploration of mtDNA function and for creating new cellular and animal models of mitochondrial disease.
Cryo-EM structure of the polycystin 2-l1 ion channel
Authors: Hulse Raymond E. , Li Zongli , Huang Rick K. , Zhang Jin , Clapham David E.
Published: March 2018

We report the near atomic resolution (3.1 Å) of the polycystic kidney disease 2-like 1 (polycystin 2-l1) ion channel. Encoded by PKD2L1, polycystin 2-l1 is a calcium and monovalent cation-permeant ion channel in primary cilia and plasma membranes. The related primary cilium-specific polycystin-2 protein, encoded by PKD2, shares a high degree of sequence similarity, yet has distinct permeability characteristics. Here we show that these differences are reflected in the architecture of polycystin 2-l1.
Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype
Authors: Ohanna Mickaël , Cerezo Mickaël , Nottet Nicolas , Bille Karine , Didier Robin , Beranger Guillaume , Mograbi Baharia , Rocchi Stéphane , Yvan-Charvet Laurent , Ballotti Robert , Bertolotto Corine
Published: March 2018

In BRAFV600E melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD+) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene. NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032. NAMPT expression induces transcriptomic and epigenetic reshufflings that steer melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies. Therefore, NAMPT, the key enzyme in the NAD+ salvage pathway, appears as a rational target in targeted therapy-resistant melanoma cells and a key player in phenotypic plasticity of melanoma cells.