bluuebunny/crossref_metadata_2025 huggingface dataset:
Curve registration
Authors: Ramsay James
Published: August 2018

This article deals with curve registration, which refers to methods for aligning prominent features in a set of curves by transforming their abscissa variables. It first illustrates the concepts of amplitude and phase variation schematically and with real data before defining the time-warping functions and their functional inverse. It then describes the decomposition of total mean squared variation into separate amplitude and phase components, along with an R2 measure of the proportion of functional variation due to phase in a sample of curves. It also considers landmark registration, novel ways of defining curve features, continuous registration, and methods based on structured models for amplitude and phase variation combined with more statistically oriented fitting methods such as maximum likelihood or Bayesian estimation. The article concludes with a brief survey of software resources for registration.
Text-to-Speech Synthesis
Authors: Dutoit Thierry , Stylianou Yannis
Published: August 2018

Text-to-speech (TTS) synthesis is the art of designing talking machines. Seen from this functional perspective, the task looks simple, but this chapter shows that delivering intelligible, natural-sounding, and expressive speech, while also taking into account engineering costs, is a real challenge. Speech synthesis has made a long journey from the big controversy in the 1980s, between MIT’s formant synthesis and Bell Labs’ diphone-based concatenative synthesis. While unit selection technology, which appeared in the mid-1990s, can be seen as an extension of diphone-based approaches, the appearance of Hidden Markov Models (HMM) synthesis around 2005 resulted in a major shift back to models. More recently, the statistical approaches, supported by advanced deep learning architectures, have been shown to advance text analysis and normalization as well as the generation of the waveforms. Important recent milestones have been Google’s Wavenet (September 2016) and the sequence-to-sequence models referred to as Tacotron (I and II).
‘The Desired Countrey’
Authors: Simpson Ken
Published: August 2018

This chapter discusses the centrality of the invisible church for Bunyan and his readers. Called to lead the Bedford congregation in 1671, Bunyan was committed to defending and building the visible church, but its purpose was to nurture souls on the pilgrimage to heaven, the invisible church of glory whose members were known only by God. Doctrinal works on the theology of justification, polemical works on ‘things indifferent’ (such as baptism) or on essentials of faith, and pastoral works on the spiritual conditions of his readers, all attest to Bunyan’s single-minded focus on the invisible church in the 1670s. Religious toleration, like the visible church, was not a good in itself but a means to an end: the ‘desired countrey’ of union with God, the imagined community outside of time that made the present an interval of remembrance and anticipation.
Piety and Radicalism
Authors: Zinck Arlette
Published: August 2018

Scholars have long debated the issue of quietism and radicalism in John Bunyan’s prose and poetry. What is one to make of a minister who exhorts Nonconformists to non-violence in his prose writings yet pens imaginative fictions—one titled The Holy War (1682)—that seemingly glorify bloody acts of social and political radicalism? This chapter looks at the extensive corpus of works published by Bunyan in the 1680s, over the course of the last eight years of his life. This chapter does this through the lens of narrative theology, arguing that an appreciation of Bunyan’s pre-critical biblical hermeneutic helps to reconceptualize the apparent contradictions in his perspectives on violence, especially during the era of renewed oppression that occurred in the early 1680s.
The Pilgrim’s Progress, Part II (1684)
Authors: Thickstun Margaret Olofson
Published: August 2018

This chapter discusses how writing The Pilgrim’s Progress, Part II (1684) allowed Bunyan to explore areas of Christian experience that Part I did not address, especially the workings of an ideal church and the spiritual lives of women, including the issue of literacy and women’s access to the Word. Anticipating a younger and female readership for this story of Christiana, her children, and her friend Mercie, Bunyan adopts in Part II a more didactic style, replacing Part I’s emphasis on testifying to spiritual experience with frequent scenes of catechizing. Great-heart the minister creates the spiritual community in Part II and guides it through a landscape far more welcoming to pilgrims than that of Part I. Because women’s ‘burdens’ are internal, connected to their sexuality, they cannot be lost, only contained through marriage, child-bearing, and obedience to male authority.
Bunyan, Emblem, and Allegory
Authors: Tambling Jeremy
Published: August 2018

This chapter discusses John Bunyan in relation to five versions of allegory, in turn: personification; allegorical narratives, and Bunyan’s use of the allegorical framework of the dream, popular in the medieval period; the concept of figura, as developed by Erich Auerbach; emblems and emblematic allegory; and pictorial symbols as allegory. Finally, the chapter considers the work of Walter Benjamin and Paul de Man, and discusses the radical uses of allegory in critiquing ideological meanings and the view that language is inherently allegorical, which destabilizes both authors and their utterance, making all expression ironic, taking irony as a form of allegory. Although focusing mainly on The Pilgrim’s Progress, the chapter also discusses Bunyan’s use of allegory in his other fictional works.
Bunyan and Romance
Authors: Davis Nick
Published: August 2018

This chapter argues that The Pilgrim’s Progress in both Part I and Part II (1678; 1684) makes creative use of the story-generative procedures of romance, in John Bunyan’s time the most socially inclusive of narrative genres, and that this signals a sympathetic attunement to the genre. Analysis of the texts’ reworking of romance focuses on transformations of narrative materials through the altering of the category under which they are to be understood, and through the setting up of cognitive dislocation in their handling. The chapter’s final section considers Bunyan’s incorporation of pervasive scriptural reference into a narrative of romance adventure.
The Language of The Pilgrim’s Progress
Authors: Coleman Julie
Published: August 2018

This analysis of John Bunyan’s language demonstrates that although he wrote The Pilgrim’s Progress (1678; 1684) in a simple style for uneducated readers, his control of the English language was far from unsophisticated. His vocabulary, eschewing recent and learned loans, ensured that the literal level of his narrative was accessible even to inexperienced readers and listeners. Disentangling normal features of contemporary language from stylistic archaism reveals how the Bible speaks through Bunyan’s work. Using biblical language not only raised the tone of The Pilgrim’s Progress, but also allowed Bunyan to habituate his readers to linguistic features that might otherwise have been off-putting when they turned to the Bible for themselves. Differences between Part I and Part II of The Pilgrim’s Progress indicate that the grammar and syntax became increasingly reflective of the language of the Bible, although in other respects Bunyan moved towards a closer representation of contemporary spoken idiom.
Bunyan and the Historians
Authors: Spargo Tamsin
Published: August 2018

This chapter offers a chronological account of varying historical and historicist approaches to the life and writings of John Bunyan from the seventeenth to the twenty-first century. The theoretical assumptions of major scholars in the field are highlighted, from a Whig such as Macaulay in the nineteenth century to a Marxist such as Christopher Hill in the twentieth, to more recent work by contemporary historians such as Richard L. Greaves and N. H. Keeble. It explores changing conceptions of the relationship between text and context, and past, present, and future, as they have informed research, analysis, historiography, and interpretation within the developing disciplines of History and of English Literature. This exploration is coupled with a consideration of the often unacknowledged relationship between teleological conceptions of history and the practice of historical research and historiography.
Bunyan Unbound
Authors: Camden Vera J.
Published: August 2018

In a 1945 letter to the British Medical Journal, D. W. Winnicott protests unethical impositions upon mental patients in which surgeons are ‘cutting brains about’. He remarks, ‘what happens if these physical therapy methods spread to the treatment of criminals? What guarantee have we that a Bunyan in prison will be allowed to keep his brain intact and his imagination free?’ Bunyan, whose resistance to the repressive authorities of his day fostered his genius, in fact flourished in prison, keeping his brain intact, his imagination free. During his long confinement, the prison walls become the scene of his dream of The Pilgrim’s Progress (1678). Drawing upon psychoanalytic theories of guilt, punishment, and creativity, this chapter offers the case of Bunyan as a Nietzschean ‘pale criminal’ whose lonely confinement quells his conscience and consolidates his identity as pastor, poet, and pilgrim.
Bunyan, Theory, and Theology
Authors: Branch Lori
Published: August 2018

This chapter makes the case for integrating theory and theology in our reading of Bunyan as fruitful for a deeper understanding of his works and as exemplary of the potential of emerging post-secular criticism. By taking up the thematic of faith in Grace Abounding (1666), The Pilgrim’s Progress (1678), and select works by Jacques Derrida, it shows how these texts illuminate faith as faith—not faith reconstituted as knowledge—as an inherent part of the linguistic condition. It claims that the particular mode of Bunyan’s literary recasting of the epistemological uncertainty faced in Grace Abounding into the fantasy form of The Pilgrim’s Progress suggests the contours of a larger understanding of the significance of fantasy fiction for Anglophone Protestant Christianity in modernity: that is, that fantasy fiction is where a spirituality that has imagined faith as knowledge embodies the fuller truth of its status as faith.
Wayfaring Images
Authors: Collé-Bak Nathalie
Published: August 2018

The Pilgrim’s Progress (1678; 1684) has been illustrated in many different forms and media, from its early days on the book market up until today. For over the last three centuries, John Bunyan’s allegory has inspired illustrators in numerous and varied ways, the images born of the text having materialized on book pages as well as on individual sheets, but also on canvas, photographic film, glass panes, and walls. Two-dimensional creations have also led the way to three-dimensional images, exhibited or performed in a variety of places and for a whole range of publics. This chapter contends that these sundry ‘illustrations’, by professional as well as amateur artists, have secured the diffusion and the popularity of the text through its temporal and geographical journeys, and across cultural boundaries.
Bunyan and the Early Novel
Authors: Wall Cynthia
Published: August 2018

The Pilgrim’s Progress (1678; 1684) is not a novel, but it comes from the same cultural swirl that produced the early novel. This chapter highlights both Bunyan’s influence on the early novel, and a seventeenth-century English culture that influenced Bunyan alongside the early novelists. The proliferation of things, the realized spaces, the vivid characters, their emblematic names, their pungent dialogues, and the metatextualities of marginalia, interpolated narratives, and self-reflexivity, all find descendants—direct, collateral, or cultural—in the deliberate repetitions of Daniel Defoe, the detailed descriptions of Eliza Haywood, the interrupting narrators of Henry Fielding, and the rhetorical patterns of every other literary genre (newspapers, histories, poems, drama) digested by the early novel.
The Pilgrim’s Progress in the Evangelical Revival
Authors: Rivers Isabel
Published: August 2018

This chapter is concerned with the ways in which evangelicals of various persuasions in the later eighteenth century—Methodists (both Arminian and Calvinist), Church of England evangelicals, and evangelical Dissenters (both Congregationalist and Baptist)—adopted The Pilgrim’s Progress as one of their key texts and made it speak to their own situations. It focuses on three main topics: first, how, in the hands of its editors, The Pilgrim’s Progress became a polemical text, especially from the 1770s onwards, one hundred years after the book’s publication; second, how it was used as a guide to Christian experience as lived by evangelicals; and third, how it became a means of writing the history of Dissent and evangelicalism. The key figures discussed include John Wesley, George Whitefield, John Newton, Richard Conyers, William Shrubsole, William Mason, George Burder, John Bradford, and Thomas Scott.
Bunyan and the Romantics
Authors: Shears Jonathan
Published: August 2018

This chapter re-examines the influence that John Bunyan exercised on some major figures of the Romantic period. It argues that while writers like Samuel Taylor Coleridge and Sir Walter Scott are rightly remembered for their role in separating theological from realistic content in the reception history of The Pilgrim’s Progress, this should not be viewed as the totality of Romantic response to Bunyan’s work. The chapter examines how the Protestant conversion narrative was developed and altered by writers like Wordsworth and Scott, and the ways in which Blake and Coleridge in particular attended carefully to, and drew imaginative inspiration from, the specific details of soteriology in The Pilgrim’s Progress. The chapter argues that while the Romantic response to Bunyan was revisionary, it was more attentive to his beliefs than some of the commentary of the period—such as Coleridge’s notorious distinction between ‘conventicle’ and ‘Parnassus’—would suggest.
Bunyan and the Bedford Congregation
Authors: Dunan-Page Anne
Published: August 2018

This chapter provides an overview of Congregational government and discipline at work in the Bedford church from its foundation in 1650 to the 1720s, and of Bunyan’s role as its minister. It uses as evidence the church’s surviving minutes, a manuscript volume entitled ‘A Booke Containing a Record of the Acts of a Congregation of Christ, in, and about Bedford’. It focuses on the definition of a Congregational church, the gathering of a congregation, the admission and excommunication of its members, as well as the role of elected officers and the question of baptism. Questions are addressed relating to Dissenting identity and the tensions that appear between the duties of men and women within a fellowship of believers, and also between what they came to regard as their own domestic, social, and spiritual interests.
Bunyan for Children
Authors: Murray Shannon
Published: August 2018

Bunyan had a profound if largely accidental influence on English children’s literature. He wrote a collection of poems for children, but it was The Pilgrim’s Progress (1678; 1684) that became a staple of the nursery shelf, adopted by children who seem to have read it more for the adventure than for the theology. Editions aimed specifically for that audience followed, and these often radically adapted Bunyan’s language, theology, and subject matter. So ubiquitous was The Pilgrim’s Progress that children’s writers such as Louisa May Alcott, Francis Hodgson Burnett, and L. M. Montgomery could assume that their readers would know Bunyan’s allegory and so could use it as a significant subtext for their own novels. While the variety and number of books for children in the twentieth century means that The Pilgrim’s Progress was read less often, there are still many versions for young readers, including pop-up books and graphic novels.
Bunyan: Class and Englishness
Authors: Day Gary
Published: August 2018

This chapter examines class and Englishness in Bunyan. It argues that interest in Bunyan and class is most evident at times of turmoil in British society, such as the 1930s, and that Bunyan’s Englishness is often linked to a sense of place, his literary achievement, and his Christianity. However, wider cultural changes mean that class and Englishness in Bunyan need to be re-examined. The Pilgrim’s Progress (1678; 1684) is shown to anticipate aspects of modern tourism and it is compared to Julian Barnes’s novel England, England (1998). The final part of this chapter, which focuses on The Life and Death of Mr. Badman (1680), looks at how an understanding of the exchange relation, as defined by Karl Marx, helps us to see the relationship between class and Englishness in the writings of Bunyan and elsewhere.
Bunyan’s Reading
Authors: Pooley Roger
Published: August 2018

The Bible is John Bunyan’s primary text, but the range of his reading, before and after his conversion experience, reveals some of the sources of his imaginative works as well as his pastoral and theological concerns. This chapter discusses, in turn, some of the key books in his intellectual and spiritual formation, including popular ballads, newsbooks, and romances; best-selling religious works by Lewis Bayly and Arthur Dent; Martin Luther’s commentary on Galatians; the terrifying story of the apostate Francis Spira; a treatise by Isaac Ambrose in which (it is claimed) he wrote marginal annotations; and John Foxe’s great ecclesiastical history, Acts and Monuments, a copy of which Bunyan had with him in prison, and to which he refers often in his writings.
Bunyan in Prison
Authors: Gay David
Published: August 2018

Prison was a difficult yet defining experience for John Bunyan. His writings of the 1660s complement the introspective mode of Grace Abounding (1666) with polemical and pastoral purposes. I Will Pray with the Spirit (?1662) is a forceful attack on the Book of Common Prayer and the regulation of worship by the restored regime. His prison poems present discrete subjects for religious meditation set within an overarching narrative framework of providential history. His writings reshape the boundaries of time and space imposed by the harsh conditions of imprisonment. Christian Behaviour (1663), The Holy City (1665), and The Resurrection of the Dead (?1665) address different aspects of Christian temporal experience under the pressure of persecution. These and other texts of the 1660s anticipate some of the main themes of Bunyan’s major allegories.
High sustained virologic response rate using generic directly acting antivirals in the treatment of chronic hepatitis C virus Egyptian patients: single-center experience
Authors: El-Nahaas Saeed M. , Fouad Rabab , Elsharkawy Aisha , Khairy Marwa , Elhossary Walied , Anwar Ismail , Abdellatif Zeinab , Maher Rabab M. , Bekheet Nader , Esmat Gamal
Published: August 2018

Background

Hepatitis C virus (HCV) is a major health problem in Egypt, with a high prevalence of genotype 4.

Aim

This study aimed to evaluate the safety and efficacy of generic sofosbuvir (SOF) plus generic daclatasvir (DAC) with or without ribavirin in the treatment of Egyptian chronic HCV patients compared with the use of brand drugs.

Materials and methods

An observational study that included 234 Egyptian chronic HCV patients was carried out. Patients were classified into two groups: group A (101 patients) received brand SOF 400 mg plus brand DAC 60 mg and group B (134 patients) received generic SOF 400 mg plus generic DAC 60 mg with or without ribavirin for 12 weeks. The end point was a sustained virological response at 12 weeks after treatment.

Results

Thirty-eight (37.2%) patients in group A were treatment experienced compared with 12 (9.02%) patients in group B; there were 39 (38%) cirrhotic patients in group A and 22 (16.5%) cirrhotic patients in group B. In group A, 50% of patients received ribavirin, while in group B, 42.1% of patients received ribavirin. All patients were followed up; all of them attended their week 12 post-treatment visit with negative HCV RNA, with achievement of sustained virological response at 12 in 100% of patients receiving generic drugs (group B) and 99% of patients receiving brand drugs (group A). Generic SOF and DAC were well tolerated, with mild adverse events including fatigue and headache.

Conclusion

Use of generic SOF and DAC with or without ribavirin is an extremely effective and a well-tolerated treatment for Egyptian chronic HCV patients.
Sofosbuvir based regimens in the treatment of chronic hepatitis C genotype 1 infection in African–American patients: a community-based retrospective cohort study
Authors: Gayam Vijay , Tiongson Benjamin , Khalid Mazin , Mandal Amrendra K. , Mukhtar Osama , Gill Arshpal , Garlapati Pavani , Shrestha Binav , Khalid Mowyad , Chakraborty Sandipan , Guss Debra , Sherigar Jagannath , Mansour Mohammed , Mohanty Smruti
Published: August 2018

Background

Direct-acting antiviral (DAA) drugs have been highly effective in the treatment of chronic hepatitis C (HCV) infection. Limited data exist comparing the safety, tolerability, and efficacy of DAAs in African–American (AA) patients with chronic hepatitis C genotype 1 (HCV GT-1) in the community practice setting. We aim to evaluate treatment response of DAAs in these patients.

Patients and methods

All the HCV GT-1 patients treated with DAAs between January 2014 and January 2018 in a community clinic setting were retrospectively analyzed. Pretreatment baseline patient characteristics, treatment efficacy with a sustained virologic response at 12 weeks post-treatment (SVR12), and adverse reactions were assessed.

Results

Two-hundred seventy-eight patients of AA descent were included in the study. One-hundred sixty-two patients were treated with ledipasvir/sofosbuvir (SOF)±ribavirin, 38 were treated with simeprevir/SOF±ribavirin, and 38 patients were treated with SOF/velpatasvir. Overall, SVR at 12 weeks was achieved in 94.6% in patients who received one of the three DAA regimens (93.8% in ledipasvir/SOF group, 92.1% in simeprevir/SOF group, and 97.4% in SOF/velpatasvir group). Previous treatment experience, HCV RNA levels and HIV status had no statistical significance on overall SVR achievement (P=0.905, 0.680, and 0.425, respectively). Compensated cirrhosis in each of the treatment groups did not influence overall SVR of 12. The most common adverse effect was fatigue (27%). None of the patients discontinued the treatment because of adverse events.

Conclusion

In the real-world setting, DAAs are safe, effective, and well tolerated in African–American patients with chronic HCV GT-1 infection with a high overall SVR rate of 94.6%. Treatment rates did not differ on the basis of previous treatment and compensated cirrhosis status.
DAIRYdb: A manually curated gold standard reference database for improved taxonomy annotation of 16S rRNA gene sequences from dairy products
Authors: Meola Marco , Rifa Etienne , Shani Noam , Delbès Céline , Berthoud Hélène , Chassard Christophe
Published: August 2018

Reads assignment to taxonomic units is a key step in microbiome analysis pipelines. To date, accurate taxonomy annotation, particularly at species rank, is still challenging due to the short size of read sequences and differently curated classification databases. However, the close phylogenetic relationship between species encountered in dairy products requires accurate species annotation to achieve sufficient phylogenetic resolution for further downstream ecological studies or for food diagnostics. Taxonomy annotation in universal 16S databases with environmental sequences like Silva, RDP or Greengenes is based on predictions rather than on studies of type strains or isolates. We provide a manually curated database composed of 10’290 full-length 16S rRNA gene sequences from prokaryotes tailored for dairy products analysis (https://github.com/marcomeola/DAIRYdb). The performance of the DAIRYdb was compared with the universal databases Silva, LTP, RDP and Greengenes. The DAIRYdb significantly outperformed all other databases independently of the classification algorithm by enabling higher accurate taxonomy annotation down to the species rank. The DAIRYdb accurately annotates over 90% of the sequences of either single or paired hypervariable regions automatically.

The manually curated DAIRYdb strongly improves taxonomic classification accuracy for microbiome studies in dairy environments. The DAIRYdb is a practical solution that enables automatization of this key step, thus facilitating the routine application of NGS microbiome analyses for microbial ecology studies and diagnostics in dairy products.
The endosomal sorting adaptor HD-PTP is required for ephrin-B:EphB signalling in cell collapse and motor axon guidance
Authors: Lahaie Sylvie , Morales Daniel , Bagci Halil , Hamoud Noumeira , Castonguay Charles-Etienne , Kazan Jalal M. , Desrochers Guillaume , Klar Avihu , Gingras Anne-Claude , Pause Arnim , Côté Jean-François , Kania Artur
Published: August 2018

The signalling output of many transmembrane receptors that mediate cell-cell communication is restricted by the endosomal sorting complex required for transport (ESCRT), but the impact of this machinery on Eph tyrosine kinase receptor function is unknown. We identified the ESCRT-associated adaptor protein HD-PTP as part of an EphB2 BioID interactome, and confirmed this association using co-immunoprecipitation. Although HD-PTP loss does not change EphB2 expression, it attenuates the ephrin-B2:EphB2 signalling-induced collapse of cultured cells and axonal growth cones, and results in aberrant guidance of chick spinal motor neuron axonsin vivoHD-PTP depletion abrogates ligand-induced EphB2 clustering, and EphB2 and Src family kinase activation. HD-PTP deficiency also accelerates ligand-induced EphB2 degradation, contrasting the phenotypes reported for other cell surface receptors. Our results link Eph signalling to the ESCRT machinery and demonstrate a role for HD-PTP in the earliest steps of ephrin-B:EphB signalling, as well as in obstructing premature receptor depletion.
Sostdc1 regulates natural killer cell maturation and cytotoxicity
Authors: Millan Alberto J. , Elizaldi Sonny R. , Lee Eric M. , Aceves Jeffrey O. , Murugesh Deepa , Loots Gabriela G. , Manilay Jennifer O.
Published: August 2018

Natural killer (NK) cells are specialized lymphocytes with the innate ability to eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified novel roles for Sclerostin domain containing-1 (Sostdc1) in NK cell development and function.Sostdc1-knockout (Sostdc1-/-) mice display a progressive accumulation of transitional NK cells (CD27+CD11b+, tNK) with age, indicating a partial developmental block. The Ly49 repertoire on NK cells inSostdc1-/-mice is also changed. Lower frequencies ofSostdc1-/-splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I+, G2+, H+and D+populations were universally decreased at the most mature (CD27-CD11b+, mNK) stage. We hypothesized that the Ly49 repertoire inSostdc1-/-mice would correlate with NK killing ability, and observed thatSostdc1-/-NK cells are hyporesponsive against MHC-I-deficient cell targetsin vitroandin vivo, despite higher CD107a surface levels and similar IFNγ expression to controls. Consistent with Sostdc1’s known role in the regulation of Wnt signaling, high levels of Wnt coactivatorsTcf7andLef1were observed inSostdc1-/-NK cells. Expression of the NK development geneId2was decreased inSostdc1-/-iNK and tNK cells, but we observed no changes inEomesandTbx21expression. Reciprocal bone marrow transplant experiments showed thatSostdc1regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both non-hematopoietic and hematopoietic sources. Taken together, these data support a role forSostdc1in the regulation of NK cell maturation, and NK cell cytotoxicity, and identify potential NK cell niches.

Summary of Results

Sostdc1-/-mice display a partial block between the tNK and mNK developmental stages.

Sostdc1influences the Ly49 receptor repertoire on NK cells.

NK cells inSostdc1-/-mice display impaired ability to killβ2m-/-target cells.

Sostdc1-/-NK cell subsets express high levels of Wnt coactivatorsTcf7andLef1.

Id2expression is decreased in iNK and tNK cells in the absence ofSostdc1.

Bone marrow transplantation experiments demonstrate cell-extrinsic regulation of NK cell maturation by Sostdc1 in both non-hematopoietic (stromal) and hematopoietic cells.
Delayed start of first-time breeding and non-breeders surplus in the Western Siberian population of the European Pied Flycatcher
Authors: Grinkov Vladimir G. , Sternberg Helmut
Published: August 2018

Non-breeders are those sexually mature individuals that do not breed in a given reproductive cycle of a population. There is a widespread belief that the presence of non-breeders can affect the actual population dynamics, as well as the population responses to environmental change (Lee et al. 2017). Sternberg (1989), using demographic data, has shown that 83% and 62% of males and females, respectively, do not breed in the first year of life in the Lower Saxony (Germany) population of the European Pied Flycatcher (Ficedula hypoleuca). Later, with experimental removal of males, it has been proven that in the Lower Saxony and Moscow Region (Russia) populations, there are many non-breeding males (Sternberg et al. 2002). For the Netherlands population of the European Pied Flycatcher, the presence of a large number of non-breeders has been demonstrated using experimental removals for both males and females (Both et al. 2017). Here we have estimated the number of non-breeders in the Western Siberian population of the European Pied Flycatcher using demographic data (11 cohorts from 2001 to 2011 of birth) and experimental removal of males. We have shown that both males and females can start to breed at the age of one to five years. The proportion of non-breeders can be 59.5% and 68.5% for first-year males and females, respectively. We discuss the differences in the proportion of non-breeders between the Western Siberian and European populations of the European Pied Flycatcher, as well as factors affecting the number of non-breeders.
Forecasting bacterial survival-success and adaptive evolution through multi-omics stress-response mapping, network analyses and machine learning
Authors: Zhu Zeyu , Surujon Defne , Pavao Aidan , Bento José , van Opijnen Tim
Published: August 2018

Whether a bacterial pathogen establishes an infection and/or evolves antibiotic resistance depends on successful survival while experiencing stress from for instance the host immune system and/or antibiotics. Predictions on bacterial survival and adaptive outcomes could thus have great prognostic value. However, it is unknown what information is required to enable such predictions. By developing a novel network-based analysis method, a bacterium's phenotypic and transcriptional response can be objectively quantified in temporal 3D-feature space. The resulting trajectories can be interpreted as a degree of coordination, where a focused and coordinated response predicts bacterial survival-success, and a random uncoordinated response predicts survival-failure. These predictions extend to both antibiotic resistance and in vivo infection conditions and are applicable to both Gram-positive and Gram-negative bacteria. Moreover, through experimental evolution we show that the degree of coordination is an adaptive outcome - an uncoordinated response evolves into a coordinated response when a bacterium adapts to its environment. Most surprisingly, it turns out that phenotypic and transcriptional response data, network features and genome plasticity data can be used to train a machine learning model that is able to predict which genes in the genome will adapt under nutrient or antibiotic selection. Importantly, this suggests that deterministic factors help drive adaptation and that evolution is, at least partially, predictable. This work demonstrates that with the right information predictions on bacterial short-term survival and long-term adaptive outcomes are feasible, which underscores that personalized infectious disease diagnostics and treatments are possible, and should be developed.
Predicting the future direction of cell movement with convolutional neural networks
Authors: Nishimoto Shori , Tokuoka Yuta , Yamada Takahiro G , Hiroi Noriko F , Funahashi Akira
Published: August 2018

Image-based deep learning systems, such as convolutional neural networks (CNNs), have recently been applied to cell classification, producing impressive results; however, application of CNNs has been confined to classification of the current cell state from the image. Here, we focused on cell movement where current and/or past cell shape can influence the future cell fate. We demonstrate that CNNs prospectively predicted the future direction of cell movement with high accuracy from a single image patch of a cell at a certain time. Furthermore, by visualizing the image features that were learned by the CNNs, we could identify morphological features, e.g., the protrusions and trailing edge that have been experimentally reported to determine the direction of cell movement. Our results indicate that CNNs have the potential to predict the future cell fate from current cell shape, and can be used to automatically identify those morphological features that influence future cell fate.
Contrast sensitivity reveals an oculomotor strategy for temporally encoding space
Authors: Casile Antonino , Victor Jonathan , Rucci Michele
Published: August 2018

The contrast sensitivity function (CSF), how sensitivity varies with the spatial frequency of the stimulus, is a fundamental assessment of visual performance. The CSF is generally assumed to be determined by low-level sensory processes. However, the sensitivities of neurons in the early visual pathways, as measured in experiments with immobilized eyes, diverge from psychophysical CSF measurements in primates. Under natural viewing conditions, as in typical psychophysical measurements, humans continually move their eyes, drifting in a seemingly erratic manner even when looking at a fixed point. Here, we show that the resulting transformation of the visual scene into a spatiotemporal flow on the retina constitutes a processing stage that reconciles human CSF and the response characteristics of retinal ganglion cells under a broad range of conditions. Our findings suggest a fundamental integration between perception and action: eye movements work synergistically with the sensitivities of retinal neurons to encode spatial information.
Candidate genes under balancing selection in a plant bacterial pathogen
Authors: Castillo José A. , Agathos Spiros N.
Published: August 2018

Plant pathogens are under significant selective pressure by the plant host. Consequently, they are expected to have adapted to this condition or contribute to evading plant defenses. In order to acquire long-term fitness, plant bacterial pathogens are usually forced to maintain advantageous genetic diversity in populations. This strategy ensures that different alleles in the pathogen’s gene pool are maintained in a population at frequencies larger than expected under neutral evolution. This selective process, known as balancing selection, is the subject of this work in the context of a common plant bacterial pathogen. We performed a genome-wide scan ofRalstonia solanacearum,an aggressive plant bacterial pathogen that shows broad host range and causes a devastating disease called ‘bacterial wilt’. Using a sliding window approach, we analyzed 57 genomes from three phylotypes ofR. solanacearumto detect signatures of balancing selection. A total of 161 windows showed extreme values in three summary statistics of population genetics: Tajima’s D, Watterson’s θ and Fu & Li’s D*. We discarded any confounding effects due to demographic events by means of coalescent simulations of genetic data. The prospective windows correspond to 78 genes that map in any of the two main replicons ofR. solanacearum.The candidate genes under balancing selection are related to primary metabolism (51.3%) or directly associated to virulence (48.7%), being involved in key functions targeted to dismantle plant defenses or to participate in critical stages in the pathogenic process. These genes are useful to understand and monitor the evolution of bacterial pathogen populations and emerge as potential candidates for future treatments to induce specific plant immune responses.
Transposable Element Exprssion in Tumors is Associated with Immune Infiltration and Increased Antigenicity
Authors: Kong Yu , Rose Chris , Cass Ashley A. , Darwish Martine , Lianoglou Steve , Haverty Pete M. , Tong Ann-Jay , Blanchette Craig , Mellman Ira , Bourgon Richard , Greally John , Jhunjhunwala Suchit , Albert Matthew L. , Chen-Harris Haiyin
Published: August 2018

Profound loss of DNA methylation is a well-recognized hallmark of cancer. Given its role in silencing transposable elements (TEs), we hypothesized that extensive TE expression occurs in tumors with highly demethylated DNA. We developed REdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observed increased expression of over 400 TE subfamilies, of which 262 appeared to result from a proximal loss of DNA methylation. The most recurrent TEs were among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent resulted in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing both inflammation and the display of potentially immunogenic neoantigens.

One Sentence Summary

Transposable element expression in tumors is associated with increased immune response and provides tumor-associated antigens
A speech envelope landmark for syllable encoding in human superior temporal gyrus
Authors: Oganian Yulia , Chang Edward F.
Published: August 2018

Listeners use the slow amplitude modulations of speech, known as the envelope, to segment continuous speech into syllables. However, the underlying neural computations are heavily debated. We used high-density intracranial cortical recordings while participants listened to natural and synthesized control speech stimuli to determine how the envelope is represented in the human superior temporal gyrus (STG), a critical auditory brain area for speech processing. We found that the STG does not encode the instantaneous, moment-by-moment amplitude envelope of speech. Rather, a zone of the middle STG detects discrete acoustic onset edges, defined by local maxima in the rate-of-change of the envelope. Acoustic analysis demonstrated that acoustic onset edges reliably cue the information-rich transition between the consonant-onset and vowel-nucleus of syllables. Furthermore, the steepness of the acoustic edge cued whether a syllable was stressed. Synthesized amplitude-modulated tone stimuli showed that steeper edges elicited monotonically greater cortical responses, confirming the encoding of relative but not absolute amplitude. Overall, encoding of the timing and magnitude of acoustic onset edges in STG underlies our perception of the syllabic rhythm of speech.
Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer
Authors: Trigos Anna S. , Pearson Richard B. , Papenfuss Anthony T. , Goode David L.
Published: August 2018

Extensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumours, we show many transcriptional changes in tumours are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent point mutations were enriched in regulator genes linking unicellular and multicellular subnetworks, while copy-number alterations affected downstream target genes in distinctly unicellular and multicellular regions of the GRN. Our results depict drivers of tumourigenesis as genes that created key regulatory links during the evolution of early multicellular life, whose dysfunction creates widespread dysregulation of primitive elements of the GRN. Several genes we identified as important in this process were associated with drug response, demonstrating the potential clinical value of our approach.
Flexibly-oriented double Cdc45-MCM-GINS intermediates during eukaryotic replicative helicase maturation
Authors: Liu Lu , Zhang Yue , Zhang Jingjing , Wang Jian-Hua , Cao Qinhong , Li Zhen , Campbell Judith L. , Dong Meng-Qiu , Lou Huiqiang
Published: August 2018

The core of the eukaryotic helicase MCM is loaded as an inactive double hexamer (DH). How it is assembled into two active Cdc45-MCM-GINS (CMG) helicases remains elusive. Here, we report that at the onset of S phase, both Cdc45 and GINS are loaded as dimers onto MCM DH, resulting in formation of double CMG (d-CMG). As S phase proceeds, d-CMGs gradually mature into two single CMG-centered replisome progression complexes (RPCs). Mass spectra reveal that RPA and DNA Pol α/primase co-purify exclusively with RPCs, but not with d-CMGs. Consistently, d-CMGs are not able to catalyze either the unwinding or de novo DNA synthesis, while RPCs can do both. Using single-particle electron microscopy, we have obtained 2D class averages of d-CMGs. Compared to MCM DHs, they display heterogeneous, flexibly orientated and partially loosened conformations with changed interfaces. The dumbbell-shaped d-CMGs are mediated by Ctf4, while other types of d-CMGs are independent of Ctf4. These data suggest CMG dimers as bona fide intermediates during MCM maturation, providing an additional quality control for symmetric origin activation and bidirectional replication.
High-throughput characterisation of bull semen motility using differential dynamic microscopy
Authors: Jepson Alys , Arlt Jochen , Statham Jonathan , Spilman Mark , Burton Katie , Wood Tiffany , Poon Wilson C. K. , Martinez Vincent A.
Published: August 2018

We report a high-throughput technique for characterising the motility of spermatozoa using differential dynamic microscopy. A large field of view movie (~ 10mm2) records thousands of cells (e.g. ≈ 5000 cells even at a low cell density of 20 × 106cells/ml) at once and yields averaged measurements of the mean (υ) and standard deviation (σ) of the swimming speed, a head oscillation amplitude (A0) and frequency (f0), and the fraction of motile spermatozoa (α). Interestingly, the measurement ofαrelies on the swimming spermatozoa enhancing the motion of the non-swimming population. We demonstrate the ease and rapidity of our method by performing on-farm characterisation of bull spermatozoa motility, and validate the technique by comparing laboratory measurements with tracking. Our results confirm the long-standing theoretical prediction thatfor swimming spermatozoa.
Crystal growth, a research-driven laboratory course
Authors: Whelan Jamie , Koussa Joseph , Chehade Ibrahim , Sabanovic Merima , Chang Adrienne , Carelli Daniel , An Zhihua , Zhang Lu , Bernstein Joel , Rabeh Wael M.
Published: August 2018

The research-driven laboratory experiment described herein has at its core the individual development of students, combining core subject matter with the opportunity to explore, in a research environment, areas outside of traditional curricula; however, it maintains the pedagogical training for an undergraduate major degree in chemistry and sciences in general. The laboratory can feasibly be implemented in high schools to expose students to an engaging and intellectually fulfilling aspect of chemistry early in their career. This seven-week project is based on the growth and study of crystals and encourages students, from the outset, to conceive, propose, design, plan and carry out their own research on chemicals and conditions of their own choosing. The wide array of laboratory equipment, analytical instrumentation and techniques that the students are potentially exposed to, from micropipettes and optical microscopes to scanning electron microscopy and powder X-ray diffraction, puts these projects on a par with senior capstone research projects. The feedback from the students for the seven years this project has been in operation is almost unanimous in enthusiasm and praise.
Characterization of Pd/Y multilayers with B4C barrier layers using GIXR and X-ray standing wave enhanced HAXPES
Authors: Wu M.-Y. , Huang Q.-S. , Le Guen K. , Ilakovac V. , Li B.-X. , Wang Z.-S. , Giglia A. , Rueff J.-P. , Jonnard P.
Published: August 2018

Pd/Y multilayers are high-reflectance mirrors designed to work in the 7.5–11 nm wavelength range. Samples, prepared by magnetron sputtering, are deposited with or without B4C barrier layers located at the interfaces of the Pd and Y layers to reduce interdiffusion, which is expected from calculating the mixing enthalpy of Pd and Y. Grazing-incident X-ray reflectometry is used to characterize these multilayers. B4C barrier layers are found to be effective in reducing Pd–Y interdiffusion. Details of the composition of the multilayers are revealed by hard X-ray photoemission spectroscopy with X-ray standing wave effects. This consists of measuring the photoemission intensity from the samples by performing an angular scan in the region corresponding to the multilayer period and an incident photon energy according to Bragg's law. The experimental results indicate that Pd does not chemically react with B nor C at the Pd–B4C interface while Y does react at the Y–B4C interface. The formation of Y–B or Y–C chemical compounds could be the reason why the interfaces are stabilized. By comparing the experimentally obtained angular variation of the characteristic photoemission with theoretical calculations, the depth distribution of each component element can be interpreted.