bluuebunny/crossref_metadata_2025 huggingface dataset:
Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism
Authors: Bagnéris Claire , DeCaen Paul G. , Naylor Claire E. , Pryde David C. , Nobeli Irene , Clapham David E. , Wallace B. A.
Published: May 2014

Significance

Many drugs used to treat pain, epilepsy, and cardiac arrhythmias target human voltage-gated sodium-selective channels. Surprisingly, we found that a bacterial voltage-gated sodium channel is also inhibited by many eukaryotic sodium channel antagonists. This bacterial channel was crystallized with several brominated blocker compounds, and the high-resolution structures reveal a common antagonist binding site in the cavity of the pore. Electrophysiology studies of channels with mutations at adjacent residues validate the site. These results suggest that despite millions of years of evolution separating human and bacterial sodium channels, these simple bacterial channels can be a valuable tool for screening and rational design of human drugs.
Structural analysis and characterization of new small serum proteins from the serum of a venomous snake (Gloydius blomhoffii)
Authors: Shioi Narumi , Deshimaru Masanobu , Terada Shigeyuki
Published: May 2014

Some snakes have several anti-toxic proteins in their sera that neutralize their own venom. Five new small serum proteins (SSPs) were isolated from Japanese mamushi (Gloydius blomhoffii) serum by gel-filtration and RP-HPLC, and their N-Terminal sequences were determined. The amino acid sequences of the precursor proteins were deduced from the nucleotide sequences of cDNAs encoding them. Due to the sequence similarity to those of SSPs in habu snake (Protobothrops flavoviridis) serum (>75% identity), these proteins were designated mSSP-1 to mSSP-5 as the homologs of habu proteins. mSSP-1 was stable at 100 °C and in the pH range of 1–10, and inhibited the proteolytic activity of a certain snake venom metalloproteinase. The inhibitory activity was extinguished by modifying the amino groups of mSSP-1. mSSP-1 is the first prostate secretory protein of the 94 amino acid-family protein with a carbohydrate chain in the Asn37 residue.
Decay Theory of Immediate Memory: From Brown (1958) to Today (2014)
Authors: Ricker Timothy J. , Vergauwe Evie , Cowan Nelson
Published: May 2014

This work takes a historical approach to discussing Brown's (1958) paper, “Some Tests of the Decay Theory of Immediate Memory”. This work was and continues to be extremely influential in the field of forgetting over the short term. Its primary importance is in establishing a theoretical basis to consider a process of fundamental importance: memory decay. Brown (1958) established that time-based explanations of forgetting can account for both memory capacity and forgetting of information over short periods of time. We discuss this view both in the context of the intellectual climate at the time of the paper's publication and in the context of the modern intellectual climate. The overarching theme we observe is that decay is as controversial now as it was in the 1950s and 1960s.
Adults see vision to be more informative than it is
Authors: Wang J. Jessica , Miletich Dongo Diana , Ramsey Richard , Samson Dana
Published: May 2014

Humans gain a wide range of knowledge through interacting with the environment. Each aspect of our perceptual experiences offers a unique source of information about the world—colours are seen, sounds heard and textures felt. Understanding how perceptual input provides a basis for knowledge is thus central to understanding one's own and others’ epistemic states. Developmental research suggests that 5-year-olds have an immature understanding of knowledge sources and that they overestimate the knowledge to be gained from looking. Without evidence from adults, it is not clear whether the mature reasoning system outgrows this overestimation. The current study is the first to investigate whether an overestimation of the knowledge to be gained from vision occurs in adults. Novel response time paradigms were adapted from developmental studies. In two experiments, participants judged whether an object or feature could be identified by performing a specific action. Adult participants found it disproportionately easy to accept looking as a proposed action when it was informative, and difficult to reject looking when it was not informative. This suggests that adults, like children, overestimate the informativeness of vision. The origin of this overestimation and the implications that the current findings bear on the interpretation of children's overestimation are discussed.
Global days of action, global public transcripts and democracy
Authors: Gregoratti Catia
Published: May 2014

Democracy and global democracy figure prominently in a number of global manifestos and petitions, which were released in conjunction with the global days and months of action taking place between 2011 and 2012. Drawing primarily on James Scott, I examine the production, circulation and contestation of three global public transcripts invoking democracy – the Manifesto for Global Democracy, the Global May Manifesto and the People's Petition. I bring to light the subterranean politics of global post-2010 activisms revealing alliances and divisions in the construction of meanings ascribed to global democracy. I extend this argument exploring the relations between intellectuals and protesting commoners, highlighting how intellectuals have contributed to the circulation of practices and language of democracy within contemporary social protests, and to the ascription of diverging meanings to democracy and its concrete possibilities.
The rhetoric of neoliberalism in the politics of crisis
Authors: Crines Andrew Scott
Published: May 2014

This is the first article to compare directly Margaret Thatcher's and David Cameron's rhetoric of neoliberalism in the context of global economic crises. By doing so, it highlights similar rhetorical arguments used to justify the liberalisation of the British economy, each striving to emphasise the ‘common sense’ nature of neoliberalism by comparing it to household economies and a broader sense of economic simplicity, and each is presented as the sole solution to economic crises. The structure of the analysis focuses on the modes of persuasion ethos, pathos and logos, whilst acknowledging the importance of the political and ideological context in each period. The article concludes that, although similarities exist in their rhetorical strategies, differing political circumstances shaped the particular features of Thatcher's and Cameron's discourses.
Pronormal subgroups and zeros of characters
Authors: Navarro Gabriel
Published: May 2014

We give a characterization of when a pronormal subgroup of a solvable group is normal by using character theory.
Descent of restricted flat Mittag–Leffler modules and generalized vector bundles
Authors: Estrada Sergio , Guil Asensio Pedro , Trlifaj Jan
Published: May 2014

A basic question for any property of quasi–coherent sheaves on a scheme

X
X

is whether the property is local, that is, it can be defined using any open affine covering of

X
X

. Locality follows from the descent of the corresponding module property: for (infinite dimensional) vector bundles and Drinfeld vector bundles, it was previously proved by Kaplansky’s technique of dévissage. Since vector bundles coincide with

ℵ
0

\aleph _0

–restricted Drinfeld vector bundles, a question arose as to whether locality holds for

κ
\kappa

–restricted Drinfeld vector bundles for each infinite cardinal

κ
\kappa

. We give a positive answer here by replacing the dévissage with its recent refinement involving

C

\mathcal C

–filtrations and the Hill Lemma.
Introduction
Authors: Raith Charles
Published: May 2014

The introductory chapter lays the framework for understanding the significance and methodology of the analysis of Calvin’s and Aquinas’s commentaries on Romans. It engages current scholarship on Calvin and the topic of soteriological participation and demonstrates why the present book is a needed correction to this field of study. The chapter then provides necessary historical and theological qualifications for properly conducting a comparative analysis of Aquinas and Calvin on Romans. It then discusses the significance of Paul’s letter to the Romans for both Aquinas and Calvin and concludes with a summary of the chapters that follow.
Abraham
Authors: Raith Charles
Published: May 2014

This chapter highlights the implications of Aquinas’s and Calvin’s readings of Romans 1–3 for their respective interpretations of father Abraham. Important for their interpretations of Romans 4 is whether justification enables the believer to participate in Christ’s justice according to the believer’s own mode of existence (Aquinas), or whether God’s forgiveness of sins and the imputation of Christ’s righteousness should be contrasted with the possession of the quality of justness (Calvin). The difference between these two interpretive moves means that Calvin draws a strong contrast between justification by faith and merit, as well as between justification by faith and by works, while Aquinas affirms justification by faith without drawing the contrast with merit and works. Informing Calvin’s criticisms against merit is his interpretation of meritorious acts in competitive-causal terms, with human willing occurring in autonomous terms, separate from God’s causal activity.
Defining prosody
Authors: Ladd D. Robert
Published: May 2014

The term prosody has been used with greatly varying meanings. The term was coined in classical times to refer to the word accents of ancient Greek, but gradually spread to cover many phonetic features that were not represented in alphabetic writing, including intonation, rhythm, and pausing or phrasing, and then the structure of verse. In modern linguistics, the term (especially in the adjectival form prosodic) has undergone a comparable expansion since the early twentieth century, implicitly based on what is represented in IPA segmental transcription, and with few attempts to provide a serious definition. There are a number of oppositions that may provide defining criteria, including filter vs. source, verbal vs. non-verbal, short domain vs. long domain, and paradigmatic vs. syntagmatic. However, it is difficult to avoid the conclusion that prosody consists of at least two distinct subsets of phenomena, the broadly autosegmental and the broadly metrical.
On duality of patterning
Authors: Ladd D. Robert
Published: May 2014

Language is often said to exhibit ‘duality of patterning’ (Hockett) or ‘double articulation’ (Martinet): an open-ended inventory of meaningful elements (morphemes or words) is composed of a closed inventory of meaningless ones (phonemes). But the definition of this design feature is elusive, and it is often conflated with productivity or arbitrariness. These confusions betray the influence of widespread unexamined assumptions about phonology, including the idea that all distinctive phonetic properties of a language are exhaustively incorporated in a closed inventory of phonemes, and the idea that phonological structure is essentially linear. These ideas are incompatible with the nature of analogues to phonology in signed languages and Chinese writing. The essence of duality of patterning is a distinction between linguistic structures composed of meaningful elements (morphology and syntax) and the internal structure of meaningful elements themselves (phonology)
Knowing What To Do
Authors: Chappell Timothy
Published: May 2014

This book develops a picture of what philosophical ethics can be like, once set from the idealizing and reductive pressures of conventional moral theory. Its question is ‘How are we to know what to do?’, and its answer is ‘By developing our moral imaginations’. The series of studies that constitute this book contribute to the case that the imagination is a key part of human excellence or virtue by showing that it plays a wide variety of different roles in our practical and evaluative lives. There is no short-cut or formulaic way of knowing what to do; but the longer and more painstaking approach is more rewarding anyway. This approach involves developing our repertoire of natural human capacities for imagination, open deliberation, and contemplative attention to the world, the people, and the reality of value around us.
Introduction
Authors: Chappell Sophie Grace
Published: May 2014

Introduces and summarizes the rest of the book. Introduces the central themes: in particular the contrast between negative critique of systematic moral theory, and the positive project of replacing it with something else. Connections are made with the previously-pursued project of making out the notion of an ‘ethical outlook’. Three particular defects of systematic moral theory are noted: intellectual imperialism, detail in the wrong place, and motivational dryness.
Beauty and Nobility in Ethics
Authors: Chappell Sophie Grace
Published: May 2014

Continuing the project begun in Chapter 7, of suggesting ways in which we might expand our repertoire of (recognized) ethical concepts, this chapter develops the idea that tou kalou heneka, ‘for the sake of The Fine’, or ‘The Beautiful’, is a name for one important kind of practical-rational intelligibility. Or rather, several important kinds: there are plenty of complexities within the idea which it will be interesting to explore. One thing we can learn from these explorations is that our practical reasons are much less structured, much more piecemeal, particular, and bitty, than moral philosophers generally like to think. Another lesson is one way to answer the familiar question ‘Why be moral?’
A Conceptual Framework for Technology-Assisted Music Learning
Authors: Bauer William I.
Published: May 2014

This chapter serves as an introduction to the book and the Technological Pedagogical and Content Knowledge (TPACK) conceptual framework around which the book is designed. The discussion situates the use of technology for music learning within a context of technology’s role in general education, society, and our daily lives. Drawing on the research literature, the point is made that technology hasn’t become a truly integrated aspect of many music classrooms. Taking the position that a major reason for this is that most music teachers don’t have the complete knowledge and skill set (TPACK) necessary to effectively incorporate technology into classes and rehearsals, the TPACK model is introduced as an approach that may be advantageous. The model is explained, with applications to music provided.
Creating Music
Authors: Bauer William I.
Published: May 2014

Grounded in the research and best practice literature, chapter 3 discusses concepts and skills, pedagogies, and technology related to musical creativity. Creativity is usually an assumed part of being musical. While there are creative aspects to a variety of musical activities – for instance developing an interpretation of a musical composition involves creative thinking – the focus in this chapter is on the development of original musical ideas through two primary musical processes, improvisation and composition. The chapter provides an overview of creativity, discusses the process of learning to improvise and compose, describes pedagogical strategies to use with students, and suggests technological tools that can support creative musical experiences. Contemporary approaches to musical creativity such as remixing and mashups are also addressed.
Responding to Music
Authors: Bauer William I.
Published: May 2014

Grounded in the research and best practice literature, chapter 5 discusses concepts and skills, pedagogies, and technologies related to human response to music. All people respond to music in a variety of ways. Music educators strive to develop students’ abilities to listen to and describe music, analyze and evaluate it, understand its historical and cultural contexts, and appreciate its relationships to other disciplines, including other art forms. Numerous technological tools are capable of supporting student learning in these aspects of music. They may also provide a means to respond to musical stimuli. By aligning musical outcomes related to responding to music with appropriate pedagogies and supporting technologies, music educators can assist students in their continuing development of knowledge and skills essential for meaningful, lifelong involvement with music.
Instructional Design
Authors: Bauer William I.
Published: May 2014

Learning is contextual, active, social, and reflective. Learners construct their own understanding by connecting prior knowledge to new information. Technology, when properly utilized, can facilitate these natural learning processes. This chapter discusses fundamental principles of human learning as they apply to the design of lessons, units, and curricula that include technology. Design models described include project based learning and backwards design, two approaches that often utilize technology and value the development of student 21st century skills such as creativity, critical thinking, communication, and collaboration. Technology is also a tool music educators can use to differentiate instruction and to provide learning support to special needs students. Finally, when engaged in instructional design that includes technology, music educators and their students need to be cognizant of copyright laws, utilizing public domain and Creative Commons media and materials whenever possible.
Productivity and Professional Development
Authors: Bauer William I.
Published: May 2014

There are numerous ways in which technology can improve the productivity of music educators, helping to make administrative and organizational tasks more efficient and effective. This chapter describes a variety of technological tools that can be used to facilitate overall organization, communication, public relations and advocacy, the creation and acquisition of instructional support materials, data management, travel, and maintenance of financial records, all of which are typical responsibilities of music teachers. Technology can also be useful for continuing professional development. From informal Personal Learning Networks to formalized graduate degree programs, technology can empower music educators with personalized, sustained, flexible, and social professional learning opportunities. Taken together, these approaches to professional development can help music educators continually develop and refine their TPACK, facilitating an ongoing upward spiral of the knowledge and skills necessary for music learning today.
Being an Emerging Christian
Authors: Marti Gerardo , Ganiel Gladys
Published: May 2014

This chapter features the stories of Emerging Christians, honing in on their personal, often individualized, experiences of deconstruction, often characterized as deconversion stories. Emerging Christians nurture a shared deconstructed religious orientation by participating in reoriented religious communities that draw on long-established and well-understood structures of institutionalized Christianity. The chapter emphasizes the common experiences of Emerging Christians, such as disillusionment with evangelicalism, megachurches, or rigid mainline denominations; and the liberating effects reported from reading Brian McLaren books. Emerging Christians are finding newly legitimated ways to move out of conventional Christian expectations. Emerging Christians continually balance the dual demands of deconstructing their individual faith and investing in cooperative congregational relationships. Rather than cultivating communities in which they can lose themselves or find a means to adopt a larger collective identity, Emerging Christians join emerging congregations that promote a religiously individualized self, one that strives for a type of nonconformity that commingles ambiguity and conviction. Because being an Emerging Christian is a form of personal religiosity that is expected to be intentionally (rather than customarily) enacted, this type of religious self cannot avoid being strategic in its activities. We therefore describe their actions as the enactment of a strategic religiosity.
Deconstructing Congregational Practices
Authors: Marti Gerardo , Ganiel Gladys
Published: May 2014

Hybridity is characteristic of the practices of emerging congregations, including pub churches, neo-monastic communities, religious arts collectives, and other more recognizably “congregational” expressions. At first glance, the practices of emerging congregations appear as eclectic, even anything goes approaches to Christianity. But it is not simply the case that Emerging Christians pick from the practices that they like without regard for how these practices will have an impact on their personal development and on communal, congregational life. Rather, all the practices found in emerging congregations are chosen carefully and strategically, with a view to embodying the ideals inherent to the wider “conversation.” In their approaches to preaching, leadership, liturgy, and the physical locations and appearances of church, emerging congregations are embodying their critiques of evangelicalism, seeker megachurches, and mainline congregations. In their diverse and varied practices we can see Emerging Christians’ deconstruction of these expressions of Christianity worked out and reassembled into something new, while still rooted within Christian traditions. The capacity for multiply achieved hybridity in turn reflects the heterogeneity of the religious organizational field from which Emerging Christians have been eager to draw on new (to them) practices or to reimagine old ones.
Following Jesus in the Real World
Authors: Marti Gerardo , Ganiel Gladys
Published: May 2014

This chapter explores how Emerging Christians live—or strive to live—in the real world. The test of whether people are Christians is not whether they assent to specific intellectual beliefs and doctrines but rather their everyday lives outside official church spaces. This has been identified as a shift from orthodoxy (right belief) to orthopraxis (right practice). Some Emerging Christians choose lifestyles that they see as inherently political, believing that this is the best way for them to practice Christianity. For them, Jesus’s mission was a political one on behalf of the poor and marginalized, so they seek to emulate Jesus by identifying with disadvantaged communities, or working for peace and reconciliation, through conventional political engagement, forming neo-monastic communities, creating Temporary Autonomous Zones, and choosing careers which promote social justice. For others, it implies a move toward a religion-less Christianity, where religious institutions and meetings become less important as people focus on loving others outside church. Overall, immersive relationships with people outside their congregations and involvements with loftier ethical and political concerns provide Emerging Christians multiple, necessary opportunities for experimenting and implementing a newly individuated religious self.
Understanding Emerging Christianity
Authors: Marti Gerardo , Ganiel Gladys
Published: May 2014

The Emerging Church Movement (ECM) is best understood as an intriguing reshaping of religious imperatives and the efforts to put them into practice. The book not only synthesizes the broader argument of the book but also places it in contrast to common interpretations of the ECM, such as that it is merely evangelicalism in disguise, liberal Protestantism in another guise, religious consumerism, or a movement that has already run its course. The book argues that the structure and practices of Emerging Christianity represent a distinctive approach to religious individualization. We describe the religious orientation or “self” of the Emerging Christian as “legitimate,” “sacralized,” and “pluralist,” which is supported by congregations that facilitate a cooperative egoism. Emerging congregations provide settings where pluralism is embraced and where the otherwise isolated self can find meaning and fulfillment through others. In the ways it has responded to modernity, the ECM (and the other expressions of Christianity it may influence) is remarkably well-adapted to persist, even thrive, as a viable religious alternative in the West. And the patterns of religious individualism, the formation of pluralist congregations, the allowance for multiple forms of legitimate spirituality, and the desire to strategically construct a personal faith that is valid and strengthened by life lived in the real world will be a ubiquitous element of modern religiosity.
Food Insufficiency and Income Volatility in US Households: The Effects of Imputed Income in the Survey of Income and Program Participation
Authors: Dahl Molly , DeLeire Thomas , Mok Shannon
Published: May 2014

In this article, we explore how using imputed income data in the Survey of Income and Program Participation affects the observed relationship between household income volatility and food insufficiency. We find that measuring income volatility using imputed income data substantially understates the association between large drops in household income and food insufficiency. After excluding observations with imputed income, large drops in income are associated with a 2.1–percentage point increased probability of food insufficiency, or a 31% higher likelihood of food insufficiency.
HTML5 PivotViewer: high-throughput visualization and querying of image data on the web
Authors: Taylor Stephen , Noble Roger
Published: May 2014

Motivation:  Visualization and analysis of large numbers of biological images has generated a bottle neck in research. We present HTML5 PivotViewer, a novel, open source, platform-independent viewer making use of the latest web technologies that allows seamless access to images and associated metadata for each image. This provides a powerful method to allow end users to mine their data.

Availability and implementation:  Documentation, examples and links to the software are available from http://www.cbrg.ox.ac.uk/data/pivotviewer/ . The software is licensed under GPLv2.

Contact:   stephen.taylor@imm.ox.ac.uk and roger@coritsu.com
Role of Physical Activity in the Relationship Between Mastery and Functional Health
Authors: Sargent-Cox Kerry A. , Butterworth Peter , Anstey Kaarin J.
Published: May 2014

Purpose of the Study:

To examine the influence of mastery, physical activity levels, and subsequent trajectories of domains of functional health across the adult life course.

Design and Methods:

We examined 8-year trajectories of physical functioning (handgrip strength) and functional health (physical [RAND PHC12], psychological [RAND MHC12], and cognitive [processing speed]) in a large Australian sample (n = 7,485 at baseline) of 3 cohorts (20–24, 40–44, and 60–64 years). Within- and between-person indirect effects of physical activity on the relationship between mastery and health were examined using multilevel structural equation models.

Results:

Mastery was positively related to within-person change in physical and psychological health for all cohorts, and processing speed for the 60s. Between-person mastery was positively associated with all health domains across all cohorts. Physical activity indirectly influenced the between-person relationships between mastery and handgrip strength, physical health, and psychological health in all cohorts, and between mastery and processing speed for the 60s.

Implications:

Psychological resources are important mechanisms for functional health as they may drive adaptive behaviors such as physical activity. The within-person association connecting mastery with physical and psychological health trajectories provides promise for interventions that foster or improve a sense of mastery. The findings contribute to the understanding of complex relationships between personal resources and behaviors that aid in successful aging across the life span.
Firm detection of a cyclotron resonance feature with Suzaku in the X-ray spectrum of GRO J1008−57 during a giant outburst in 2012
Authors: Yamamoto Takayuki , Mihara Tatehiro , Sugizaki Mutsumi , Nakajima Motoki , Makishima Kazuo , Sasano Makoto
Published: May 2014

We report on the firm detection of a cyclotron resonance scattering feature (CRSF) in the X-ray spectrum of the Be X-ray binary pulsar, GRO J1008−57, achieved by the Suzaku Hard X-ray Detector during a giant outburst which was detected by the MAXI Gas Slit Camera in 2012 November. The Suzaku observation was carried out on 2012 November 20, outburst maximum when the X-ray flux reached ∼ 0.45 Crab in 4–10 keV, which corresponds to a luminosity of 1.1 × 1038 erg s−1 in 0.5–100 keV at 5.8 kpc. The obtained broadband X-ray spectrum from 0.5 keV to 118 keV revealed a significant absorption feature, considered as the fundamental CRSF, at ∼ 76 keV. This unambiguously reconfirms the previously suggested ∼ 80 keV spectral feature in GRO J1008−57. The implied surface magnetic field, 6.6 × 1012 G, is the highest among binary X-ray pulsars from which CRSFs have ever been detected.
A Single-institution Comparison of Cetuximab, Carboplatin, and Paclitaxel Induction Chemotherapy Followed by Chemoradiation (CRT) Versus CRT for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LA-SCCHN)
Authors: Grover Surbhi , Mitra Nandita , Wan Fei , Lukens John N. , Sharma Sonam , Bauman Jessica , Masroor Farzad , Cohen Roger B. , Desai Arati , Algazy Kenneth , Alonso-Basanta Michelle , Ahn Peter , Kevin Teo Boon-Keng , Chalian Ara A. , Weinstein Gregory S. , O’Malley Bert W. , Lin Alexander
Published: May 2014

Objectives:

Comparisons of induction chemotherapy (IC) against upfront chemoradiation (CRT) for locally advanced head and neck cancer (LA-HNSCC) have demonstrated no differences except greater toxicity with IC. Effective induction regimens that are less toxic are therefore warranted. To inform future efforts with IC, we present our institutional experience comparing a less toxic IC regimen to CRT.

Methods:

We included patients with LA-HNSCC treated with organ-preservation CRT (+/−induction) between 2008 and 2011. Patients were of age above 18 years, ECOG performance status 0-1, and had minimum 6 months follow-up. IC consisted of 8 weekly cycles of cetuximab, carboplatin, and paclitaxel followed by CRT. The CRT regimen was platinum based, with cetuximab reserved for patients contraindicated to receive platinum.

Results:

Of 118 patients, 24 (20%) received IC and 94 (80%) received CRT. Median follow-up was 17 (IC) and 19 (CRT) months (P=0.05). There were no differences in toxicity between the groups. IC patients were more likely male, with more advanced tumor and nodal stage. Even when controlling for these factors, IC was still associated with worse locoregional control (HR=3.6, P=0.02), distant metastasis–free survival (HR=5.3, P=0.02), and overall survival (HR=5.1, P<0.01).

Conclusions:

IC patients had greater disease burden than those receiving CRT. IC was well tolerated, but with significant rates of locoregional and systemic failures. Given the retrospective nature of the study, our findings are not meant to be definitive or conclusive, but rather suggestive in directing future efforts with IC. For now, we favor CRT as the standard option for treatment of inoperable LA-HNSCC.
Patterns of Utilization of Complementary and Alternative Medicine in 2 Pediatric Gastroenterology Clinics
Authors: Adams Denise , Schiffgen Miriam , Kundu Anjana , Dagenais Simon , Clifford Tammy , Baydala Lola , King W. James , Vohra Sunita
Published: May 2014

Objectives:

The aim of the present study was to assess the prevalence and patterns of complementary and alternative medicine (CAM) use among pediatric patients with gastrointestinal (GI) disorders at academic clinics in Canada.

Methods:

The survey was carried out at 2 hospital‐based gastroenterology clinics: the Stollery Children's Hospital in Edmonton and the Children's Hospital of Eastern Ontario (CHEO) in Ottawa.

Results:

CAM use at the Stollery was 83% compared with 36% at CHEO (P < 0.001). The most common reason for not using CAM was lack of knowledge about it. Most respondents felt comfortable discussing CAM in their clinic and wanted more information on CAM. The most common CAM products being taken were multivitamins (91%), calcium (35%), vitamin C (32%), probiotics (14%), and fish oil/omega‐3 fatty acids (13%). The most common CAM practices being used were massage (43%), chiropractic (27%), faith healing (25%), and relaxation (18%). Most respondents believed that CAM was helpful, and most of the 23 reported adverse effects were minor. Seven were reported as moderate, and 3 were reported as severe. Many (42%) patients used CAM at the same time as prescription medicines, and of these patients, concurrent use was discussed with their physician (76%) or pharmacist (52%).

Conclusions:

CAM use is high among pediatric patients with GI disorders and is much greater among those in Edmonton than in Ottawa. Most respondents reported their CAM use as helpful, with little or no associated harm. Many patients fail to disclose their concurrent use of CAM and conventional medicines to their doctors, increasing the likelihood of interactions.
Automatic yield-line analysis of slabs using discontinuity layout optimization
Authors: Gilbert Matthew , He Linwei , Smith Colin C. , Le Canh V.
Published: May 2014

The yield-line method of analysis is a long established and extremely effective means of estimating the maximum load sustainable by a slab or plate. However, although numerous attempts to automate the process of directly identifying the critical pattern of yield-lines have been made over the past few decades, to date none has proved capable of reliably analysing slabs of arbitrary geometry. Here, it is demonstrated that the discontinuity layout optimization (DLO) procedure can successfully be applied to such problems. The procedure involves discretization of the problem using nodes inter-connected by potential yield-line discontinuities, with the critical layout of these then identified using linear programming. The procedure is applied to various benchmark problems, demonstrating that highly accurate solutions can be obtained, and showing that DLO provides a truly systematic means of directly and reliably automatically identifying yield-line patterns. Finally, since the critical yield-line patterns for many problems are found to be quite complex in form, a means of automatically simplifying these is presented.
LIMIX: genetic analysis of multiple traits
Authors: Lippert Christoph , Casale Franceso Paolo , Rakitsch Barbara , Stegle Oliver
Published: May 2014

Multi-trait mixed models have emerged as a promising approach for joint analyses of multiple traits. In principle, the mixed model framework is remarkably general. However, current methods implement only a very specific range of tasks to optimize the necessary computations. Here, we present a multi-trait modeling framework that is versatile and fast: LIMIX enables to flexibly adapt mixed models for a broad range of applications with different observed and hidden covariates, and variable study designs. To highlight the novel modeling aspects of LIMIX we performed three vastly different genetic studies: joint GWAS of correlated blood lipid phenotypes, joint analysis of the expression levels of the multiple transcript-isoforms of a gene, and pathway-based modeling of molecular traits across environments. In these applications we show that LIMIX increases GWAS power and phenotype prediction accuracy, in particular when integrating stepwise multi-locus regression into multi-trait models, and when analyzing large numbers of traits. An open source implementation of LIMIX is freely available at:https://github.com/PMBio/limix.
IVT-seq reveals extreme bias in RNA-sequencing
Authors: Lahens Nicholas F. , Kavakli Ibrahim Halil , Zhang Ray , Hayer Katharina , Black Michael B. , Dueck Hannah , Pizarro Angel , Kim Junhyong , Irizarry Rafael , Thomas Russell S. , Grant Gregory R. , Hogenesch John B.
Published: May 2014

Background

RNA sequencing (RNA-seq) is a powerful technique for identifying and quantifying transcription and splicing events, both known and novel. However, given its recent development and the proliferation of library construction methods, understanding the bias it introduces is incomplete but critical to realizing its value.

Results

Here we present a method, in vitro transcription sequencing (IVT-seq), for identifying and assessing the technical biases in RNA-seq library generation and sequencing at scale. We created a pool of > 1000in vitrotranscribed (IVT) RNAs from a full-length human cDNA library and sequenced them with poly-A and total RNA-seq, the most common protocols. Because each cDNA is full length and we show IVT is incredibly processive, each base in each transcript should be equivalently represented. However, with common RNA-seq applications and platforms, we find ∼50% of transcripts have > 2-fold and ∼10% have > 10-fold differences in within-transcript sequence coverage. Strikingly, we also find > 6% of transcripts have regions of high, unpredictable sequencing coverage, where the same transcript varies dramatically in coveragebetweensamples, confounding accurate determination of their expression. To get at causal factors, we used a combination of experimental and computational approaches to show that rRNA depletion is responsible for the most significant variability in coverage and that several sequence determinants also strongly influence representation.

Conclusions

In sum, these results show the utility of IVT-seq in promoting better understanding of bias introduced by RNA-seq and suggest caution in its interpretation. Furthermore, we find that rRNA-depletion is responsible for substantial, unappreciated biases in coverage. Perhaps most importantly, these coverage biases introduced during library preparation suggest exon level expression analysis may be inadvisable.
Differences in sensitivity to EGFR inhibitors could be explained by described biochemical differences between oncogenic Ras mutants
Authors: Stites Edward C.
Published: May 2014

Emerging data suggest different activating Ras mutants may have different biological behaviors. The most striking example may be in colon cancer, where activating KRAS mutations generally indicate a lack of benefit to treatment with EGFR inhibitors, although the activating KRAS G13D mutation appears to be an exception. As KRAS G13D generally shares the same biochemical defects as the other oncogenic KRAS mutants, a mechanism for differential sensitivity is not apparent. Here, a previously developed mathematical model of Ras mutant signaling is used to investigate this problem. The purpose of the analysis is to determine whether differential response is consistent with known mechanisms of Ras signaling, and to determine if any known features of Ras mutants provide an explanation for differential sensitivity. Computational analysis of the mathematical model finds that differential response to upstream inhibition between cancers with different Ras mutants is indeed consistent with known mechanisms of Ras biology. Moreover, model analysis demonstrates that the subtle biochemical differences between G13D and G12D (and G12V) mutants are sufficient to enable differential response to upstream inhibition. Simulations suggest that wild-type Ras within the G13D mutant context is more effectively inhibited by upstream inhibitors than when it is in the G12D or G12V contexts. This difference is a consequence of an elevated Kmfor the G13D mutant. The identification of a single parameter that influences sensitivity is significant in that it suggests an approach to evaluate other, less common, Ras mutations for their anticipated response to upstream inhibition.
Evolution of the Phosphoenolpyruvate Carboxylase Protein Kinase Family in C3 and C4 Flaveria spp.
Authors: Aldous Sophia H. , Weise Sean E. , Sharkey Thomas D. , Waldera-Lupa Daniel M. , Stühler Kai , Mallmann Julia , Groth Georg , Gowik Udo , Westhoff Peter , Arsova Borjana
Published: May 2014

The key enzyme for C4 photosynthesis, Phosphoenolpyruvate Carboxylase (PEPC), evolved from nonphotosynthetic PEPC found in C3 ancestors. In all plants, PEPC is phosphorylated by Phosphoenolpyruvate Carboxylase Protein Kinase (PPCK). However, differences in the phosphorylation pattern exist among plants with these photosynthetic types, and it is still not clear if they are due to interspecies differences or depend on photosynthetic type. The genus Flaveria contains closely related C3, C3-C4 intermediate, and C4 species, which are evolutionarily young and thus well suited for comparative analysis. To characterize the evolutionary differences in PPCK between plants with C3 and C4 photosynthesis, transcriptome libraries from nine Flaveria spp. were used, and a two-member PPCK family (PPCKA and PPCKB) was identified. Sequence analysis identified a number of C3- and C4-specific residues with various occurrences in the intermediates. Quantitative analysis of transcriptome data revealed that PPCKA and PPCKB exhibit inverse diel expression patterns and that C3 and C4  Flaveria spp. differ in the expression levels of these genes. PPCKA has maximal expression levels during the day, whereas PPCKB has maximal expression during the night. Phosphorylation patterns of PEPC varied among C3 and C4  Flaveria spp. too, with PEPC from the C4 species being predominantly phosphorylated throughout the day, while in the C3 species the phosphorylation level was maintained during the entire 24 h. Since C4  Flaveria spp. evolved from C3 ancestors, this work links the evolutionary changes in sequence, PPCK expression, and phosphorylation pattern to an evolutionary phase shift of kinase activity from a C3 to a C4 mode.
The first structure of a bacterial diterpene cyclase: CotB2
Authors: Janke Ronja , Görner Christian , Hirte Max , Brück Thomas , Loll Bernhard
Published: May 2014

Sesquiterpenes and diterpenes are a diverse class of secondary metabolites that are predominantly derived from plants and some prokaryotes. The properties of these natural products encompass antitumor, antibiotic and even insecticidal activities. Therefore, they are interesting commercial targets for the chemical and pharmaceutical industries. Owing to their structural complexity, these compounds are more efficiently accessed by metabolic engineering of microbial systems than by chemical synthesis. This work presents the first crystal structure of a bacterial diterpene cyclase, CotB2 from the soil bacteriumStreptomyces melanosporofaciens, at 1.64 Å resolution. CotB2 is a diterpene cyclase that catalyzes the cyclization of the linear geranylgeranyl diphosphate to the tricyclic cyclooctat-9-en-7-ol. The subsequent oxidation of cyclooctat-9-en-7-ol by two cytochrome P450 monooxygenases leads to bioactive cyclooctatin. Plasticity residues that decorate the active site of CotB2 have been mutated, resulting in alternative monocyclic, dicyclic and tricyclic compounds that show bioactivity. These new compounds shed new light on diterpene cyclase reaction mechanisms. Furthermore, the product of mutant CotB2W288Gproduced the new antibiotic compound (1R,3E,7E,11S,12S)-3,7,18-dolabellatriene, which acts specifically against multidrug-resistantStaphylococcus aureus. This opens a sustainable route for the industrial-scale production of this bioactive compound.
CrowdPhase: crowdsourcing the phase problem
Authors: Jorda Julien , Sawaya Michael R. , Yeates Todd O.
Published: May 2014

The human mind innately excels at some complex tasks that are difficult to solve using computers alone. For complex problems amenable to parallelization, strategies can be developed to exploit human intelligence in a collective form: such approaches are sometimes referred to as `crowdsourcing'. Here, a first attempt at a crowdsourced approach for low-resolutionab initiophasing in macromolecular crystallography is proposed. A collaborative online game namedCrowdPhasewas designed, which relies on a human-powered genetic algorithm, where players control the selection mechanism during the evolutionary process. The algorithm starts from a population of `individuals', each with a random genetic makeup, in this case a map prepared from a random set of phases, and tries to cause the population to evolve towards individuals with better phases based on Darwinian survival of the fittest. Players apply their pattern-recognition capabilities to evaluate the electron-density maps generated from these sets of phases and to select the fittest individuals. A user-friendly interface, a training stage and a competitive scoring system foster a network of well trained players who can guide the genetic algorithm towards better solutions from generation to generationviagameplay.CrowdPhasewas applied to two synthetic low-resolution phasing puzzles and it was shown that players could successfully obtain phase sets in the 30° phase error range and corresponding molecular envelopes showing agreement with the low-resolution models. The successful preliminary studies suggest that with further development the crowdsourcing approach could fill a gap in current crystallographic methods by making it possible to extract meaningful information in cases where limited resolution might otherwise prevent initial phasing.
The demand for credit, credit rationing and the role of microfinance
Authors: Cheng Enjiang , D. Ahmed Abdullahi
Published: May 2014

Purpose

– The purpose of this study is to examine the demand for credit and credit rationing conducted by formal, informal and emerging microfinance lenders in the four poor counties of China.

Design/methodology/approach

– This paper extends the existing studies on credit rationing in rural China by comparing the determinants of credit rationing by three different lenders, the formal lenders rural credit cooperatives (RCCs), the informal lenders and the new microfinance institutions (MFIs).

Findings

– MFIs are capable of reaching out to the even poorer households if they develop the loan products based on the income and expenditure flows of these households.

Research limitations/implications

– The determinants of credit rationing by three types of institutions are estimated separately.

Practical implications

– RCCs in China shall change their policy of discrimination against female-headed households. RCCs shall also simplify the loan application procedures and assess the clients based on their repayment capacities rather than the age or assets alone. RCCs could learn from MFIs to use incomes from migrant workers as a criterion to assess the loan applicants.

Social implications

– gender equity for loan access.

Originality/value

– This paper extends the existing studies on credit rationing in rural China by comparing the determinants of credit rationing by three different lenders, the formal lenders (RCCs), the informal lenders and the new MFIs.