bluuebunny/crossref_metadata_2025 huggingface dataset:
Byzantine Law
Authors: Stolte Bernard
Published: August 2018

This chapter sets out to show that Byzantine law is part of a common European past. The Byzantines identified themselves as Romans, their law was Roman law, and their capital Constantinople was the New Rome. This is clearly demonstrated by the history of Byzantine law, in which the Emperor Justinian occupies a prominent place and the legal language continued to employ Latin technical terms. With the spread of (Orthodox) Christianity in eastern Europe, Byzantine law was adopted as well. Thus we may see there, just as in the Latin west, a process of reception of Roman law on the shared basis of the Corpus iuris civilis, via a different channel.
The Beginnings of the English Common Law (To 1350)
Authors: Brand Paul
Published: August 2018

In the last quarter of the twelfth century a new type of royal court was created in England with courts possessing nationwide jurisdiction, whose justices required specific authorization to hear individual cases and who began regularly to use jury verdicts for fact-finding. From the first the justices of these new courts kept written records and from the last quarter of the thirteenth century these are supplemented by unofficial law reports made by those listening to what was done in court. Initially these courts were concerned mainly with serious crime and property rights over land but they also came to exercise jurisdiction over disputes about the mutual obligations of lords and tenants and helped to control various forms of coercion and self-help. These new courts created the English common law and well before 1350 this had also spread (to a greater or lesser extent) outside England to Ireland, Wales, and Scotland.
Russian Law in the Early Modern Period
Authors: Muravyeva Maryanna
Published: August 2018

The chapter gives an overview of the development of early modern Russian law. During this period, Russian law was undergoing a definite modernization which intensified in the seventeenth and, particularly, in the eighteenth century. The law became more rational, predictable and efficient. Russia actively engaged in codification and systematization of law, and that led to the more regular application of procedure and better lawyering. Russian law quickly adapted to the social, economic and political challenges, as it was under constant revision. Legal rules became more uniform and unvarying in their application. The Russian legal system grew to be hierarchical and bureaucratic, staffed by professionals via either practice or education. Due to these changes, the legal reforms of the nineteenth century allowed the Russian Empire to become a Rechtsstaat, although it was widely criticized and often even denied by contemporaries and scholars.
Colonial and Indigenous ‘Laws’—The Case of Britain’s Empires, C.1750–1850
Authors: Hickford Mark
Published: August 2018

This chapter argues that indigenous and colonial ‘laws’ were made and adapted in and through entanglements of peoples and dynamic political-normative regimes or epistemic communities. These underlying complexities might be obscured in extant anglophone high-level treatises or colonial judicial decisions, let alone indigenous participation in introduced colonial forums, but remain important to appreciate. In approaching the multiple ‘legalities’ in play one needs to remain conscious of how pre-existing communities interacted dynamically with strangers from across the seas. In examining these points the chapter considers several broad, intermingling phenomena: firstly, key jurisdictional tensions (including those associated with notions of ‘protection’); secondly, the evolution of strategies for governing or administering territory; and, thirdly, the regulation of proprietary interests.
The Law of the European Union in Historical Perspective
Authors: Lindseth Peter
Published: August 2018

This chapter focuses on EU public law—that is, on the structural and procedural law of public institutions, as well as their relation to each other and to private actors. It seeks to answer a specific question: whether, from a historical perspective, EU public law is best viewed as an extension of international, constitutional, or administrative law. It opts primarily for the latter rubric, setting out a historiographical theory for understanding the process of European integration as an extension of the development of modern administrative governance on the national level over the course of the twentieth century. By linking European governance to the development of administrative governance, one can begin to see the basic truth in Alan Milward’s famous, though controversial, assertion that European integration is really just ‘one more stage in the long evolution of the European state’.
The Scottish Common Law
Authors: Simpson Andrew R C
Published: August 2018

Twelfth-century Scottish monarchs laid the foundations of the medieval Scottish common law. This chapter begins by exploring the political context from which that common law emerged. It then considers the various legal tools, courts, and procedures that were created by twelfth- and early thirteenth-century monarchs to deliver royal justice. Subsequently the chapter explores how later monarchs adapted the institutions laid down by their predecessors to develop the common law of the thirteenth, fourteenth, and fifteenth centuries. Particular reference is made to the brieves, many of which were inspired in their content by near-contemporary English writs. The extent to which these ‘brieves’ furnished litigants with truly ‘common’ mechanisms for the enforcement of claims across the Scottish kingdom is currently debated, as is explained in this chapter. Finally, brief reference is made to the transformation of the common law in light of Romano-canonical learning during the fifteenth and sixteenth centuries.
Institutions of Ancient Roman Law
Authors: Colognesi Luigi Capogrossi
Published: August 2018

This chapter gives a rapid overview of the history of Roman public and private institutions, from their early beginning in the semi-legendary age of the kings to the later developments of the Imperial age. A turning point has been the passage from the kingdom to the republic and the new foundation of citizenship on family wealth, instead of the exclusiveness of clan and lineages. But still more important has been the approval of the written legislation of the XII Tables giving to all citizens a sufficient knowledge of the Roman legal body of consuetudinary laws. From that moment, Roman citizenship was identified with personal freedom and the rule of law. Following political and military success, between the end of IV and the first half of III century bce Rome was capable of imposing herself as the central power in Italy and the western Mediterranean. From that moment Roman hegemony was exercised on a growing number of cities and local populations, organized in the form of Roman of Latin colonies or as Roman municipia. Only in the last century bce were these different statutes unified with the grant of Roman citizenship to all Italians. In this same period the Roman civil law, which was applied to private litigants by the Roman praetors, had become a very complex and sophisticated system of rules. With the empire the system did not change abruptly, although the Princeps did concentrate in his hands the last power of the judiciary and became the unique source of new legislation. In that way, for the first time, the Roman legal system was founded on rational and coherent schemes, becoming a model, which Antiquity transmitted to the late medieval Europe.
The Phenomenological Approach
Authors: Moran Dermot
Published: August 2018

Phenomenology as an approach emerges with the work of Edmund Husserl and was developed in original ways by Martin Heidegger, Jean-Paul Sartre, Maurice Merleau-Ponty, Alfred Schutz, and others, to become one of the major philosophical movements of the twentieth century. Phenomenology begins from the recognition that conscious life is intentional, that is, that all conscious awareness is directed at something, and that there is a complex correlation between the subjective act and the object apprehended, such that the object is said to be “constituted” by the subject. In order to lay bare this intentional constitution, phenomenologists apply a procedure of bracketing or phenomenological reduction that strips away presuppositions embedded in the natural attitude. Phenomenology has wide application not just in philosophy but in psychology and psychiatry. In recent years, phenomenology’s stress on the embodied character of life in the context of a life-world has had a major impact on cognitive science.
Private Sector
Authors: Murphy Craig N.
Published: August 2018

The UN’s relations with the private sector initially followed the pattern of the League of Nations in occasionally relying on funding from business leaders or their foundations. In the 1970s, the UN had a more confrontational approach to transnational corporations and established a code of conduct for their operations. This approach ended in the 1990s, when the UN began subcontracting some activities both to NGOs and TNCs. Secretary-General Kofi Annan sought to collaborate with companies to enforce global human rights, labor, and environmental standards through the Global Compact, a body endorsed by thousands of companies but with little impact. Nonetheless, cooperative partnerships with private companies have become a characteristic way in which the UN delivers development services.
Media
Authors: Crossette Barbara
Published: August 2018

With a new Secretary-General, António Guterres, installed in 2017, the United Nations is in a position to hasten changes to its public information system and functions, which were slow to catch up with a fast-moving social media age. As the former head of UNHCR, he understands the importance of good relations with the media, which often have felt shut out by UN officials and member nations reluctant to expand the organization’s information outreach. Media attention had atrophied, at a time when the UN was coming under greater pressure and criticism for its handling of peacekeeping scandals and slow responses to crises, even when these were not the fault of the Secretariat.
Terrorism
Authors: Boulden Jane
Published: August 2018

Terrorism is a tool of non-state actors and as such poses a particular threat to the United Nations as a state-based organization. This chapter examines the responses of the General Assembly, Security Council, and Secretary-General to terrorism. While the Security Council has taken the lead, all three actors have made an effort to develop a sustained response to the phenomenon. Recent developments on the ground have prompted questions about the potential threat of terrorism to peace operations, as well as an emphasis on prevention. While the UN response is significant, it parallels rather than leads actions by its member states.
Human Rights
Authors: Samarsinghe Natalie
Published: August 2018

This chapter discusses the UN’s role in creating the international human rights system, with descriptions of key UN human rights instruments, mechanisms and bodies (notably the Human Rights Council), as well as information on other parts of the organization tasked with promoting and protecting human rights. It also considers opportunities and challenges for norm development and institutional advances over the next decade. The chapter argues that while human rights are recognized as one of the UN’s main purposes, with every member state having some degree of involvement with human rights laws and machinery, this area remains a source of contention, raising issues of legitimacy, universality, and sovereignty. At the same time, this so-called pillar of the UN has produced some of the organization’s most transformative successes, at the normative level and on the ground.
Humanitarian Action and Coordination
Authors: Crisp Jeff
Published: August 2018

This chapter provides a historical perspective on the role of the United Nations in the areas of humanitarian action and coordination. It examines the UN’s emerging engagement in this domain in the aftermath of the Second World War, as well as the growth of the organization’s humanitarian role during the period of decolonization in the 1960s and 1970s. The chapter argues that the end of the Cold War created a humanitarian landscape that was more complex and dangerous than had previously been the case, giving rise to a range of acute policy dilemmas in relation to the protection and provision of assistance to refugees, displaced people, and other civilians. The chapter suggests that effective interagency coordination has been a chronic challenge for the UN in the humanitarian realm and provides a critical review of the different organizational arrangements that have been established to address this concern.
UN Development System
Authors: Fomerand Jacques , Dijkzeul Dennis
Published: August 2018

This chapter presents an overview of the UN coordination machinery in the economic and social development field together with an analysis of its evolution and recurring operational problems of fragmentation, effectiveness, and duplication. Changing conceptions of security, a growing concern for the sustainability of peace and prevention, and a corresponding need for greater coherence and integration and collaborative and strategic partnerships, offer cautious grounds for optimism. But the capacity for internal leadership in improving coordination at headquarters and field levels is likely to be sharply constrained by the world organization’s decentralized structure, donor incentives, limited resources, and the absence of a political consensus about its desirable role in the promotion of development.
Prospects for UN Renovation and Reform
Authors: Luck Edward C.
Published: August 2018

This chapter traces and assesses how the four principal inter-governmental organs of the United Nations—the General Assembly, Security Council, ECOSOC, and Trusteeship Council—have changed to meet new challenges and demands. Despite their resistance to formal structural reform, each has proven adept at renovation and adaptation to dynamic conditions. As the more open and rigorous process for selecting a new Secretary-General in 2015–2016 demonstrated, relations among the principal organs remain an area for further renovation in the years ahead. Although slow to reform its structure, the Security Council has proven to be the quickest to adapt its working methods to a changing security environment.
Trusteeship Council
Authors: Wilde Ralph
Published: August 2018

The Trusteeship Council, a UN principal organ, is responsible for the Trusteeship System, an institutionalized form of colonial administration broadly following the League of Nations Mandates arrangements. This system came to be repudiated, alongside other forms of colonialism, by the external self-determination entitlement that emerged in international law after the creation of the UN in 1945. The present chapter details the concept of ‘trust’ in international policy; the central features of the Mandates and Trusteeship arrangements; the territories covered; the objectives and duration of the arrangements; the structure of administration and supervision; the historical controversy over South West Africa/Namibia; the self-determination entitlement; the revival of trusteeship; reform proposals; the new Peacebuilding Commission; and the continuing use of the Trusteeship Council chamber.
Religion, Extracurricular Activities, and Access to Public School Facilities
Authors: Russo Charles J.
Published: August 2018

The Equal Access Act (EAA) is a federal law enacted to permit organized groups of high school students to meet in schools during noninstructional time, periods when classes are not scheduled so that non-curriculum-related clubs can gather. The EAA was designed to remedy situations in which religious speech had been excluded from schools as a form of impermissible viewpoint discrimination. In Board of Education of Westside Community Schools v. Mergens, the Supreme Court upheld the EAA. This chapter covers the situation that existed before the EAA was enacted; the EAA itself; Mergens and later judicial developments; and the meaning of Mergens and its progeny. To date, it appears that the EAA has achieved its goal of granting equal access to religious speech even as it has been applied in ways beyond what its authors likely intended by including LGBT groups and others.
Catholic Higher Education
Authors: Galligan–Stierle Michael , Moore Paula
Published: August 2018

This chapter provides an overview of Catholic higher education in the United States, primarily the major themes that have developed in the twentieth and twenty-first centuries. It covers the history and development of these institutions, including general characteristics and trends related to students, faculty, and leadership. The authors describe the distinctive mission of Catholic higher education to support both intellectual development and faith formation among students. Special attention is given to those staff responsible for implementing this reality: Student Affairs staff, mission officers, and campus ministry staff. The authors analyze some of the major challenges confronting contemporary Catholic higher education.
Religion, Privatization, and American Educational Policy
Authors: Bordelon Janet
Published: August 2018

This chapter provides a brief history of the religious school choice lobby. The chapter explains how religionists, composed mostly of Catholics, Orthodox Jews, and evangelical Christians, came to advocate for the use of government funds for parochial schools. Leo Pfeffer and the American Jewish Congress opposed the use of federal funds for parochial schools, and by the late 1970s their advocacy had swayed the courts to prevent all but paltry sums of federal funds from going to private religious schools. This led school choice advocates to find alternative means of funding, namely tax credits and vouchers that aren’t regulated by the government. Given the growing divisions and tensions surrounding educational policy and religious constituents, we need to examine this history so we can better understand how to move forward. The chapter concludes with questions for educational policymakers concerning how the Establishment Clause of the First Amendment to the United States Constitution should inform government policy surrounding religion and education.
James and Evolution
Authors: Pearce Trevor
Published: August 2018

James was an evolutionary thinker who was critical of evolutionism; this chapter is an attempt to explain this strange state of affairs. In the first section, I will sketch James’s reaction to evolutionary ideas in the 1860s, especially those of Darwin: although he showed great interest, he stopped short of active endorsement. I will spend the bulk of the rest of the chapter detailing James’s response to the work of Herbert Spencer, seen at the time as the most important philosopher of evolution. James argued against Spencer’s evolutionism in the 1870s, but from the perspective of a broader naturalism. According to James, Spencer ignored important mental phenomena, in particular subjective interests and selective attention. Finally, I will briefly discuss how James deployed evolutionary ideas in his later writings on ethics and pragmatism. Although James opposed—often on scientific grounds—much of the philosophical work inspired by evolution, his philosophy was nevertheless built on its own evolutionary foundation.
Mental Health
Authors: Delle Fave Antonella , Negri Luca
Published: August 2018

This chapter offers an overview of the scientific approaches to the study of mental health, starting from the historical breakthrough represented by Maria Jahoda’s emphasis on the structural differences between mental health and mental illness, and concluding with the latest theoretical models and interventions formulated within positive psychology. Attention is paid to conceptualizations of human flourishing and psychological well-being, their operationalization and assessment tools, and their use and effectiveness in interventions. Empirical findings on positive mental health features across the life span are summarized. The approach to mental health developed within Asian traditions, and specifically in the Indian medical system of Ayurveda, is discussed in relation to the Western view. New questions and challenges arising from the expansion of knowledge about positive mental health are outlined.
The Associations Between Positive Affect and Health
Authors: Hunter John F. , Cross Marie P. , Pressman Sarah D.
Published: August 2018

We present a wide array of evidence that suggests that the presence of positive affect (PA) may be associated with a variety of health outcomes. Current evidence indicates that PA is connected to longer life, lower incidence of disease, better recovery from disease, and overall better health. While the research has not conclusively determined the mechanisms that link these concepts, we review evidence that examines the various connections between PA and health to shed light on how they may interact. We also provide suggestions for future research in this area, such as focusing on the roles that specific emotions, culture, and technology may play in the relationship between PA and health. This chapter highlights foundational evidence that indicates high levels of PA are associated with better health and provides creative directions for new research within this field to take.
Classification methods for functional data
Authors: Baillo Amparo , Cuevas Antonio , Fraiman Ricardo
Published: August 2018

This article reviews the literature concerning supervised and unsupervised classification of functional data. It first explains the meaning of unsupervised classification vs. supervised classification before discussing the supervised classification problem in the infinite-dimensional case, showing that its formal statement generally coincides with that of discriminant analysis in the classical multivariate case. It then considers the optimal classifier and plug-in rules, empirical risk and empirical minimization rules, linear discrimination rules, the k nearest neighbor (k-NN) method, and kernel rules. It also describes classification based on partial least squares, classification based on reproducing kernels, and depth-based classification. Finally, it examines unsupervised classification methods, focusing on K-means for functional data, K-means for data in a Hilbert space, and impartial trimmed K-means for functional data. Some practical issues, in particular real-data examples and simulations, are reviewed and some selected proofs are given.
An Invitation to Operator-Based Statistics
Authors: Romain Yves
Published: August 2018

This article deals with operator-based statistics and its advantages. It first provides an overview of the historical and pedagogical aspects of operator-based statistics before explaining the underlying practical and theoretical motivations, along with synthetic and conceptual arguments. In particular, it develops the operator-based approach for factor multivariate analysis (and for their asymptotic studies) and offers several examples that show the value of operators in statistics. The discussion focuses on covariance operators, Hankel and Toeplitz operators, regression operators, measure-associated operators, tensor operators, and some other important categories. The article also describes noncommutative or quantum statistics and concludes with some reflections on the key notions and formulations of a "unified statistics" and projectors in (classical) statistics.
Principal component analysis for functional data
Authors: Hall Peter
Published: August 2018

This article discusses the methodology and theory of principal component analysis (PCA) for functional data. It first provides an overview of PCA in the context of finite-dimensional data and infinite-dimensional data, focusing on functional linear regression, before considering the applications of PCA for functional data analysis, principally in cases of dimension reduction. It then describes adaptive methods for prediction and weighted least squares in functional linear regression. It also examines the role of principal components in the assessment of density for functional data, showing how principal component functions are linked to the amount of probability mass contained in a small ball around a given, fixed function, and how this property can be used to define a simple, easily estimable density surrogate. The article concludes by explaining the use of PCA for estimating log-density.
The Life and Death of Mr. Badman (1680)
Authors: Engetsu Katsuhiro
Published: August 2018

At the centre of the local world of The Life and Death of Mr. Badman (1680) is an alehouse whose keeper’s son is modelled on the young Bunyan’s intimate friend in Bedford. A focus on the representation of ‘alehouse culture’ in this work leads to a consideration of the social implications of blasphemy, Sabbath-breaking, and domestic violence in Bunyan’s local community. Badman not only breaks the Sabbath himself but prevents his first godly wife from keeping it, leading to conflict in the household, and to domestic violence. The Life and Death of Mr. Badman thus tells the story—through its narrators, Attentive and Wiseman and their digressive, eye-witnessed tales of providence and judgement—of a damnable life in the making: the journey, not of a pilgrim to heaven, but of an unrepentant, blasphemous, and violent sinner to hell.
‘Truth in Meeter’
Authors: Clarke Elizabeth
Published: August 2018

Bunyan is not thought of as a good poet by many critics, but this chapter argues that his purpose in writing poetry has been misunderstood. He is trying to redefine poetry away from courtly rhetoric, and instead uses it to create passion, and to inspire a discourse that may lead to the salvation of sinners. Bunyan tends to use a rhetoric which adds emotion to mere description, for example in his writing on hell. Nonconformist verse, including hymns, tends to address children, in part because, by being more directly emotional, poetry is thought to appeal to children. This is why Bunyan uses emblem-like forms, which primarily attempt to convey ‘Truth’. Poetry is seen here as a passion-inducing discourse, which can ‘awaken’ readers, although ultimately it cannot save them.
Early Works
Authors: Walker David
Published: August 2018

This chapter is concerned with the writings John Bunyan produced in the 1650s. These include two published attacks on the Quakers, Some Gospel-Truths Opened (1656) and A Vindication of the Book Called Some Gospel-Truths Opened (1657); A Few Sighs from Hell (1658), in which he voices a radical sympathy for the poor and oppressed; and his major work of covenant theology, The Doctrine of the Law and Grace Unfolded (1659). These early works are read against the changing context of the late 1640s and the 1650s, up until the Restoration in 1660. It is in the 1650s that Bunyan acquired the literary skills necessary to become a polemicist in what was a highly charged context of religious disputation in print. These early works reveal Bunyan’s whole-hearted commitment to the godly agenda of the English Revolution.
Improving the Credibility of Educational Intervention Research
Authors: Robinson Daniel H. , Levin Joel R. , Graham Steve , Schraw Gregory , Fuchs Lynn , Vaughn Sharon R.
Published: August 2018

This article discusses various forms of research that are contemporaneously being undertaken for either investigating or establishing the efficacy of educational interventions, along with their strengths and limitations. It first explains what “credible” educational intervention research means, taking into account the importance of causal inference in intervention research methodologies, before turning to single-case intervention designs and how they can be profitably applied in a number of educational and psychological intervention research contexts. It then describes randomization as a means to enhance the scientific credibility of single-case intervention research and how theory can make intervention research more credible. Finally, it offers recommendations for conducting, analyzing, and reporting educational intervention research, with an eye toward improving its quality and associated credibility.
AKARI and IRAS: From beam corrections to SEDs
Authors: Clements David L , Rowan-Robinson Michael , Pearson Chris , Afonso Jose , Labouteiller Vianney , Farrah Duncan , Efstathiou Andreas , Greenslade Josh , Wang Lingyu
Published: August 2018

There is significant scientific value to be gained from combining AKARI fluxes with data at other far-infrared (IR) wavelengths from the Infrared Astronomical Satellite (IRAS) and Herschel missions. To be able to do this we must ensure that there are no systematic differences between the data sets that need to be corrected before the fluxes are compatible with each other. One such systematic effect identified in the Bright Source Catalog version 1 (BSCv1) data is the issue of beam corrections. We determine these for the BSC version 2 (BSCv2) data by correlating ratios of appropriate IRAS and AKARI bands with the difference in 2 Micron All Sky Survey (2MASS) J-band extended and point source magnitudes for sources cross-matched between the IRAS Faint Source Catalog (FSC), AKARI BSCv2 and 2MASS catalogs. We find significant correlations (p ≪ 10 −13) indicating that beam corrections are necessary in the 65 and 90 μm bands. We then use these corrected fluxes to supplement existing data in spectral energy distribution (SED) fits for ultraluminous infrared galaxies (ULIRGs) in the Herschel ULIRG Survey (HERUS). The addition of AKARI fluxes makes little difference to the results of simple (T, β) fits to the SEDs of these sources, though there is a general decrease in reduced χ2 values. The utility of the extra AKARI data, however, is in allowing physically more realistic SED models with more parameters to be fitted to the data. We also extend our analysis of beam correction issues in the AKARI data by examining the Herschel Reference Sample (HRS) galaxies, which have Herschel photometry from 100 to 500 μm and which are more spatially extended than the HERUS ULIRGs. 34 of the HRS sources have good Herschel SEDs and matching data from AKARI. This investigation finds that our simple 2MASS-based beam correction scheme is inadequate for these larger and more complex sources. There are also indications that additional beam corrections at 140 and 160 μm are needed for these sources, extended on scales >1′.
Screening Tools to Predict the Development of Chronic Low Back Pain: An Integrative Review of the Literature
Authors: Pauli Jena , Starkweather Angela , Robins Jo Lynne
Published: August 2018

Objective

To identify and describe available instruments that can be used to screen patients with acute or subacute low back pain for a chronic low back pain trajectory.

Design

Integrative literature review.

Methods

An electronic search of PubMed/MEDLINE, CINAHL, Cochrane Database of Systematic Reviews, and PsychINFO databases took place from May through July of 2014 using systematic search strategies to identify screening instruments developed to identify people at risk of chronic low back pain. After screening for inclusion and exclusion criteria as well as quality indicators, the identified studies were categorized based on whether the instrument measured psychological, clinical, or functional measures to predict chronic low back pain.

Results

Initial searches identified 2,274 potential articles. After assessing for duplicates, title, and abstract content, there were 129 remaining articles. Articles were further excluded after analysis of the text, for a total of 42 studies reviewed. Most instruments reviewed were unable to provide evidence of predictive power for developing chronic low back pain.

Conclusions

This review identified numerous instruments developed to assess the likelihood of chronic low back pain in acute and subacute low back pain populations. Of the instruments reviewed, the STarT Back Screening Tool and the Örebro Musculoskeletal Pain Questionnaire demonstrated superior predictive power compared with other instruments. Both screening tools offer evidence of validation, translation into different languages and international application, and usage in various health care settings and provide data on predictive power.
Construction of a novel phagemid to produce custom DNA origami scaffolds
Authors: Nafisi Parsa M , Aksel Tural , Douglas Shawn M
Published: August 2018

DNA origami, a method for constructing nanoscale objects, relies on a long single strand of DNA to act as the ‘scaffold’ to template assembly of numerous short DNA oligonucleotide ‘staples’. The ability to generate custom scaffold sequences can greatly benefit DNA origami design processes. Custom scaffold sequences can provide better control of the overall size of the final object and better control of low-level structural details, such as locations of specific base pairs within an object. Filamentous bacteriophages and related phagemids can work well as sources of custom scaffold DNA. However, scaffolds derived from phages require inclusion of multi-kilobase DNA sequences in order to grow in host bacteria, and those sequences cannot be altered or removed. These fixed-sequence regions constrain the design possibilities of DNA origami. Here, we report the construction of a novel phagemid, pScaf, to produce scaffolds that have a custom sequence with a much smaller fixed region of 393 bases. We used pScaf to generate new scaffolds ranging in size from 1512 to 10 080 bases and demonstrated their use in various DNA origami shapes and assemblies. We anticipate our pScaf phagemid will enhance development of the DNA origami method and its future applications.
Oncological and genetic factors impacting PDX model construction with NSG mice in pancreatic cancer
Authors: Guo Shiwei , Gao Suizhi , Liu Rendong , Shen Jing , Shi Xiaohan , Bai Sijia , Wang Huan , Zheng Kailian , Shao Zhuo , Liang Chuanyu , Peng Siying , Jin Gang
Published: August 2018

A patient‐derived xenograft (PDX) approach, which relies on direct transplantation of tumor specimens into an immunocompromised animal, is a commonly used method for investigating tumor therapy predictions in vivo. This study evaluated influencing factors, including clinical, oncological, and genetic variables, for a pancreatic PDX model in mice. Tumor specimens were obtained from 121 patients with pancreatic ductal adenocarcinoma who underwent surgical resection at the Changhai Pancreatic Surgery Medical Center (Shanghai, China) between April 2016 and February 2017. Pancreatic cancer (PC) samples <3 mm3 were subcutaneously implanted into the NOD/Shi‐scid/IL‐2Rγnull (NSG) mice. Once the xenograft reached 300–500 mm3 or reached 180 d after cell inoculation, the tumor was excised. Part of the tumor was subsequently transplanted to next‐generation mice, and another part was analyzed by using immunohistochemistry. Among the 121 patients with PC, tumor xenograft was successfully generated in 86 patients (71.1%). Primary tumor >3.5 cm in size was independently associated with xenograft formation rate. In addition, several enriched mutated genes within the VEGF pathway and higher microvessel density were found in the positive group (with xenograft) compared with the negative group (without xenograft). We concluded that tumor size and mutated VEGF pathway in PC are important factors affecting PDX model construction with NSG mice.—Guo, S., Gao, S., Liu, R., Shen, J., Shi, X., Bai, S., Wang, H., Zheng, K., Shao, Z., Liang, C., Peng, S., Jin, G. Oncological and genetic factors impacting PDX model construction with NSG mice in pancreatic cancer. FASEB J. 33, 873–884 (2019). www.fasebj.org
Motor cortical beta transients delay movement initiation and track errors
Authors: Little Simon , Bonaiuto James , Barnes Gareth , Bestmann Sven
Published: August 2018

Motor cortical activity in the beta range (13-30 Hz) is a hallmark signature of healthy and pathological movement, but its behavioural relevance remains unclear. Recent work in primates and human sensory cortex suggests that sustained oscillatory beta activity observed on average, may arise from the summation of underlying short-lasting, high-amplitude bursts of activity. Classical human movement-related event-related beta desynchronisation (ERD) and synchronization (ERS) may thus provide insufficient, non-dynamic, summaries of underlying focal spatio-temporal burst activity, limiting insight into their functional role during healthy and pathological movement.

Here we directly investigate this transient beta burst activity and its putative behavioural relevance for movement control, using high-precision magnetoencephalography (MEG). We quantified the subject-specific (n=8), trial-wise (n>12,000) dynamics of beta bursts, before and after movement. We show that beta activity on individual trials is dominated by high amplitude, short lasting bursts. While average beta changes generally manifest as bilaterally distributed activity (FWHM = 25mm), individual bursts are spatially more focal (FWHM = 6 mm), sporadic (1.3 −1.5/s), and transient (mean: 96 ms).

Prior to movement (the period of the classical ERD), the timing of the last pre-movement burst predicts movement onset, suggesting a role in the specification of the goal of movement. After movement (the period of the classical ERS), the first beta burst is delayed by ~100ms after a response error occurs, intimating a role in error monitoring and evaluation.

Movement-related beta activity is therefore dominated by a spatially dispersed summation of short lasting, sporadic and focal bursts. Movement-related beta bursts coordinate the retrieval and updating of movement goals in the pre- and post-movement periods, respectively.
Personal clinical history predicts antibiotic resistance in urinary tract infections
Authors: Yelin Idan , Snitser Olga , Novich Gal , Katz Rachel , Tal Ofir , Parizade Miriam , Chodick Gabriel , Koren Gideon , Shalev Varda , Kishony Roy
Published: August 2018

The prevalence of antibiotic resistance in urinary tract infections (UTIs) often renders the prescribed antimicrobial treatment ineffective, highlighting the need for personalized prediction of resistance at time of care. Here, crossing a 10-year longitudinal dataset of over 700,000 community-acquired UTIs with over 6,000,000 personally-linked records of antibiotic purchases, we show that the resistance profile of infections can be predicted based on patient-specific demographics and clinical history. Age, gender, and retirement home residence had strong, yet differential and even non-monotonic, associations with resistance to different antibiotics. Resistance profiles were also associated with the patient’s records of past urine samples and antibiotic usage, with these associations persisting for months and even longer than a year. Drug usage selected specifically for its own cognate resistance, which led indirectly, through genetic linkage, also to resistance to other, even mechanistically unrelated, drugs. Applying machine learning models, these association patterns allowed good personalized predictions of resistance, which could inform and better optimize empirical prescription of antibiotics.
Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo image- and CRISPR/Cas9-based approach
Authors: von der Heyde Benedikt , Emmanouilidou Anastasia , Mazzaferro Eugenia , Vicenzi Silvia , Höijer Ida , Klingström Tiffany , Jumaa Sitaf , Dethlefsen Olga , Snieder Harold , de Geus Eco , Ameur Adam , Ingelsson Erik , Allalou Amin , Brooke Hannah L. , den Hoed Marcel
Published: August 2018

A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV), but candidate genes in these loci remain uncharacterized. We developed an image- and CRISPR/Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in eggs from fish that transgenically express GFP on smooth muscle cells (Tg[acta2:GFP]), to visualize the beating heart. An automated analysis of repeated 30s recordings of beating atria in 381 live, intact zebrafish embryos at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and si:dkey-65j6.2 [KIAA1755]); heart rate (rgs6 and hcn4); and the risk of sinoatrial pauses and arrests (hcn4). Exposure to 10 or 25µM ivabradine – an open channel blocker of HCNs – for 24h resulted in a dose-dependent higher HRV and lower heart rate at 5 days post-fertilization. Hence, our screen confirmed the role of established genes for heart rate and rhythm (RGS6 and HCN4); showed that ivabradine reduces heart rate and increases HRV in zebrafish embryos, as it does in humans; and highlighted a novel gene that plays a role in HRV (KIAA1755).
The origins and relatedness structure of mixed infections vary with local prevalence of P. falciparum malaria
Authors: Zhu Sha Joe , Hendry Jason A. , Almagro-Garcia Jacob , Pearson Richard D. , Amato Roberto , Miles Alistair , Weiss Daniel J. , Lucas Tim C.D. , Nguyen Michele , Gething Peter W. , Kwiatkowski Dominic , McVean Gil ,   for the Pf3k Project
Published: August 2018

Individual malaria infections can carry multiple strains of Plasmodium falciparum with varying levels of relatedness. Yet, how local epidemiology affects the properties of such mixed infections remains unclear. Here, we develop an enhanced method for strain deconvolution from genome sequencing data, which estimates the number of strains, their proportions, identity-by-descent (IBD) profiles and individual haplotypes. Applying it to the Pf3k data set, we find that the rate of mixed infection varies from 29% to 63% across countries and that 51% of mixed infections involve more than two strains. Further-more, we estimate that 47% of symptomatic dual infections contain sibling strains likely to have been co-transmitted from a single mosquito, and find evidence of mixed infections propagated over successive infection cycles. Finally, leveraging data from the Malaria Atlas Project, we find that prevalence correlates within Africa, but not Asia, with both the rate of mixed infection and the level of IBD.
Systematic Analysis of Targets of Pumilio (PUM)-Mediated mRNA Decay Identifies a Role of PUM1 in Regulating DNA Damage Response Pathway
Authors: Yamada Toshimichi , Imamachi Naoto , Imamura Katsutoshi , Kawamura Takeshi , Suzuki Yutaka , Nagahama Masami , Akimitsu Nobuyoshi
Published: August 2018

RNA-binding proteins (RBPs) play a pivotal role in gene expression by modulating the stability of transcripts; however, the identification of degradation targets of RBPs remains difficult. Here, we identified 48 target mRNAs of human Pumilio 1 (PUM1), an evolutionally conserved RBP, by combined analysis of transcriptome-wide mRNA stabilities and the binding of mRNAs to PUM1. Here, we developed an approach to identify mRNA targets of Pumilio 1 (PUM1), an evolutionally conserved RBP. By combined analysis of transcriptome-wide mRNA stabilities and the binding of mRNAs to PUM1, we identified 48 mRNAs that both bound to PUM1 and exhibited PUM1-dependent degradation. Analysis of changes in the abundance of PUM1 and its targets in RNA-seq data indicated that DNA-damaging agents negatively regulated PUM1-mediated mRNA decay. Cells exposed to cisplatin had reduced PUM1 abundance and increasedPCNAandUBE2AmRNAs, encoding proteins involved in DNA repair by translesion synthesis (TLS). Cells overexpressing PUM1 exhibited impaired DNA synthesis and TLS and increased sensitivity to the cytotoxic effect of cisplatin. Thus, our method identified targets of PUM1-mediated decay and revealed that cells respond to DNA damage by inhibiting PUM1-mediated mRNA decay to activate TLS.
Rapid Diagnosis of Lower Respiratory Infection using Nanopore-based Clinical Metagenomics
Authors: Charalampous Themoula , Richardson Hollian , Kay Gemma L. , Baldan Rossella , Jeanes Christopher , Rae Duncan , Grundy Sara , Turner Daniel J. , Wain John , Leggett Richard M. , Livermore David M. , O’Grady Justin
Published: August 2018

Lower respiratory infections (LRIs) accounted for three million deaths worldwide in 2016, the leading infectious cause of mortality. The “gold standard” for investigation of bacterial LRIs is culture, which has poor sensitivity and is too slow to guide early antibiotic therapy. Metagenomic sequencing potentially could replace culture, providing rapid, sensitive and comprehensive results. We developed a metagenomics pipeline for the investigation of bacterial LRIs using saponin-based host DNA depletion combined with rapid nanopore sequencing. The first iteration of the pipeline was tested on respiratory samples from 40 patients. It was then refined to reduce turnaround and increase sensitivity, before testing a further 41 samples. The refined method was 96.6% concordant with culture for detection of pathogens and could accurately detect resistance genes with a turnaround time of six hours. This study demonstrates that nanopore metagenomics can rapidly and accurately characterise bacterial LRIs when combined with efficient human DNA depletion.
Systematic dissection of biases in whole-exome and whole-genome sequencing reveals major determinants of coding sequence coverage
Authors: Barbitoff Yury A. , Polev Dmitrii E. , Glotov Andrey S. , Serebryakova Elena A. , Shcherbakova Irina V. , Kiselev Artem M. , Kostareva Anna A. , Glotov Oleg S. , Predeus Alexander V.
Published: August 2018

Next generation DNA sequencing technologies are rapidly transforming the world of human genomics. Advantages and diagnostic effectiveness of the two most widely used resequencing approaches, whole exome (WES) and whole genome (WGS) sequencing, are still frequently debated. In our study we developed a set of statistical tools to systematically assess coverage of CDS regions provided by several modern WES platforms, as well as PCR-free WGS. Using several novel metrics to characterize exon coverage in WES and WGS, we showed that some of the WES platforms achieve substantially less biased CDS coverage than others, with lower within- and between-interval variation and virtually absent GC-content bias. We discovered that, contrary to a common view, most of the coverage bias in WES stems from mappability limitations of short reads, as well as exome probe design. We identified the ~ 500 kb region of human exome that could not be effectively characterized using short read technology. We also showed that the overall power for SNP and indel discovery in CDS region is virtually indistinguishable for WGS and best WES platforms. Our results indicate that deep WES (100x) using least biased technologies provides similar effective coverage (97% of 10x q10+ bases) and CDS variant discovery to the standard 30x WGS, suggesting that WES remains an efficient alternative to WGS in many applications. Our work could serve as a guide for selection of an up-to-date resequencing approach in human genomic studies.