bluuebunny/crossref_metadata_2025 huggingface dataset:
Religious Freedom, Common Schools, and the Common Good
Authors: Owens Erik
Published: August 2018

Public schools are one of the quintessential civic institutions in the United States, with extraordinary reach into citizens’ lives. Public schools are entrusted with the civic responsibility to educate students with the knowledge, skills, and values required to contribute to the common good of our diverse society. This chapter connects the civic educational mission of public schools with the political and moral tradition of the common good, with a sketch of what may be called “civic education for the common good.” The first section discusses the concept of the common good and explains why religious freedom is an essential component. The second section distinguishes between civic virtue and the civic virtues, and describes which of the latter must be inculcated in schools to sustain the former. The final section argues that the common good is best served by a form of common education that is neither homogeneous nor radically pluralistic.
Religion, Spirituality, and College Students
Authors: Rockenbach Alyssa Bryant , Park Julie J.
Published: August 2018

While religion and spirituality have played pivotal roles in shaping US higher education since its inception, empirical studies on college student spirituality are a relatively recent phenomenon, gaining steam in the early 2000s with landmark national studies. These studies reflect a growing interest in the inner lives of college students and their journeys for meaning and purpose. This chapter provides an overview of key studies addressing religion and spirituality in the lives of US college students. Unique patterns related to religious worldview, race/ethnicity, sexual orientation, and gender are discussed, reflecting the tremendous range of experiences among college students. The chapter also addresses the impact of college on religious and spiritual development, including the role of different campus environments and experiences, reflecting the role of peer socialization and institutional dynamics.
Religion, Spirituality, and College Faculty
Authors: Lindholm Jennifer A.
Published: August 2018

To sustain campus communities where the life of the mind and the life of the heart are mutually celebrated and supported, we must reconsider habitual perspectives and practices. Within higher education, the spiritual and religious inclinations of faculty have implications for how faculty make meaning of their work as well as for how they engage with colleagues and students. This chapter summarizes what we know about the spiritual/religious connections in faculty members’ lives. It examines how faculty members conceptualize and experience the spiritual dimension of their lives, how they perceive the intersections between spirituality and higher education, and what implications their inclinations have for undergraduate education and for faculty life within academic workplaces. It also addresses why this dimension of their lives is important to consider within the context of academic workplaces and undergraduate education. Associated implications for research and institutional practice are also discussed.
Secularism and Religion in American Education
Authors: Kahn Jonathon S.
Published: August 2018

Recent critics of the secular have presented a newly complicated account of secularity, one in which secularity and religion are seen not as separate but as mutually intertwined and interdependent. This chapter uses these new secular critics to reflect on the history and nature of a secular education. It argues that the emergence of American secular education over the course of the twentieth century was tied to power and production of knowledge that, at times, included religious moods and outlooks. Moving forward, secular education would do well to acknowledge and include those religious outlooks into its pedagogical practices. Secular education for the twenty-first century should embrace the way learning necessarily involves character formation. Vibrant modern secular education would be marked by not only the richness of its constrained disagreements, but also by reflection on how those disagreements function liturgically to shape and influence the making of community.
Pluralism in Religion and American Education
Authors: Eck Diana L. , Randall Brendan
Published: August 2018

The United States is among the most religiously diverse countries in the world. Although such diversity is not a new phenomenon, its degree and visibility have increased dramatically in the past fifty years, reigniting the debate over a fundamental civic question: What is the common identity that binds us together? How we respond to religious diversity in the context of education has enormous implications for our democratic society. To the extent that previous frameworks such as exclusion or assimilation ever were desirable or effective, they no longer are. Increased religious diversity is an established fact and growing trend. The United States needs a more inclusive and robust civic framework for religious diversity in the twenty-first century—pluralism—and this framework should be an essential component of civic education.
James and British Philosophy
Authors: Misak Cheryl
Published: August 2018

This chapter will explore how James’s pragmatism and British philosophy were intertwined during the first decades of the twentieth century. James’s influence on the Oxford pragmatist F. C.S. Schiller is well known. So is his negative impact on the Cambridge philosophers Bertrand Russell and G. E. Moore, who took themselves to be resolutely anti-pragmatist. This “Ten Years War” will be examined in some detail. But what is less known is James’s positive influence on Cambridge philosophy. We shall see that Russell made a pragmatist turn after James’s death, and that move heavily influenced the young and brilliant Frank Ramsey. In turn, Ramsey, the only philosopher Wittgenstein rated highly, influenced Wittgenstein. Those ripples of influence continued well after Ramsey’s death at the age of 26 in 1930.
Toward a Biology of Social Support
Authors: Hooker Emily D. , Zoccola Peggy M. , Dickerson Sally S.
Published: August 2018

The presence of close, supportive ties to others can have a wide range of positive effects on health; certain biological processes may play a key role in linking positive social relationships to salubrious health outcomes. In this chapter, we review the research that connects the presence of strong, supportive social ties to positive physiological functioning, with an underlying emphasis on the implications for health and disease. Cross-sectional and prospective studies demonstrate that high levels of social integration and/or social support are associated with positive biological profiles (e.g., lower levels of neuroendocrine activity, better functioning of the immune system), whereas social isolation and loneliness can have detrimental effects on these parameters. Other research provides evidence for the stress-buffering hypothesis, which states that social support exerts beneficial effects via a downregulation of stress responses, including dampened sympathetic and neuroendocrine activity. Conversely, deficient social relationships or social conflict have been linked with negative biological profiles. Emerging animal and human research suggests that oxytocin and endogenous opioids may underlie some of these physiological and health effects. Further elucidating the pathways through which social support could influence health outcomes could subsequently be used to develop theoretically sound interventions to optimize physiological functioning and health.
Benefit-Finding
Authors: Lechner Suzanne C.
Published: August 2018

Following adverse life events, many people report positive changes, sometimes referred to as Benefit Finding (BF). In its most basic sense, we are referring to people’s reports that they have changed meaningful aspects of their lives as a result of a challenging circumstance or illness. This chapter explores the historical roots of BF and highlights the dangers of using imprecise terminology while studying this phenomenon. Next, issues related to the measurement of BF, theories of how BF develops and changes over time, and whether BF is actually associated with better outcomes are reviewed. We also discuss BF interventions and provide a cautionary note about whether encouraging BF might cause more harm than good. The chapter concludes with a surprising recommendation for less, but much more thoughtful and precise, research in this area.
A Unifying Classification for Functional Regression Modeling
Authors: Ferraty Frédéric , Vieu Philippe
Published: August 2018

This article presents a unifying classification for functional regression modeling, and more specifically for modeling the link between two variables X and Y, when the explanatory variable (X) is of a functional nature. It first provides a background on the proposed classification of regression models, focusing on the regression problem and defining parametric, semiparametric, and nonparametric models, and explains how semiparametric modeling can be interpreted in terms of dimension reduction. It then gives four examples of functional regression models, namely: functional linear regression model, additive functional regression model, smooth nonparametric functional model, and single functional index model. It also considers a number of new models, directly adapted to functional variables from the existing standard multivariate literature.
Vector Integration and Stochastic Integration in Banach Spaces
Authors: Dinculeanu Nicolae
Published: August 2018

This article deals with vector integration and stochastic integration in Banach spaces. In particular, it considers the theory of integration with respect to vector measures with finite semivariation and its applications. This theory reduces to integration with respect to vector measures with finite variation which, in turn, reduces to the Bochner integral with respect to a positive measure. The article describes the four stages in the development of integration theory. It first provides an overview of the relevant notation for Banach spaces, measurable functions, the integral of step functions, and measurability with respect to a positive measure before discussing the Bochner integral. It then examines integration with respect to measures with finite variation, semivariation of vector measures, integration with respect to a measure with finite semivariation, and stochastic integrals. It also reviews processes with integrable variation or integrable semivariation and concludes with an analysis of martingales.
On Product Measures Associated with Stationary Processes
Authors: Boudou Alain , Romain Yves
Published: August 2018

This article considers the connections between product measures and stationary processes. It first provides an overview of historical facts and relevant terminology, basic concepts and the mathematical approach. In particular, it discusses random measures, the projection-valued spectral measure (PVSM), convolution products, and the association between shift operators and PVSMs. It then presents the main results and their first potential applications, focusing on stochastic integrals, the image of a random measure under measurable mapping, the existence of a transport-type theorem, and the transpose of a continuous homomorphism between groups. It also describes the PVSM associated with a unitary operator, the convolution product of two PVSMs, the unitary operators generated by a PVSM, extension of the convolution product of two PVSMs, an equation where the unknown quantity is a PVSM, and the convolution product of two random measures. The article concludes with an analysis of mathematical developments related to the previous results.
Nonparametric Methods for α-Mixing Functional Random Variables
Authors: Delsol Laurent
Published: August 2018

This article considers how functional kernel methods can be used to study α-mixing datasets. It first provides an overview of how prediction problems involving dependent functional datasets may arise from the study of time series, focusing on the standard discretized model and modelization that takes into account the functional nature of the evolution of the quantity to be studied over time. It then considers strong mixing conditions, with emphasis on the notion of α-mixing coefficients and α-mixing variables introduced by Rosenblatt (1956). It also describes some conditions for a Markov chain to be α-mixing; some useful tools that provide covariance inequalities, exponential inequalities, and Central Limit Theorem (CLT) for α-mixing sequences; the asymptotic properties of functional kernel estimators; the use of kernel smoothing methods with α-mixing datasets; and various functional kernel estimators corresponding to different prediction methods. Finally, the article highlights some interesting prospects for further research.
Grace Abounding to the Chief of Sinners (1666)
Authors: Smith Nigel
Published: August 2018

This chapter looks closely at John Bunyan’s first major narrative, his conversion account Grace Abounding to the Chief of Sinners (1666), exploring interwoven qualities of intense religious confession, especially the deep sense of sinful guilt; metaphorical vitality drawn from Bunyan’s local experience in Bedfordshire; animated, personified, medicinal citation of the Bible (and other pious books); modes of social abjection; and pursuit of the authority to speak. Grace Abounding was composed when Bunyan was in prison under the terms of the 1664 Conventicle Act, and hence he was using the conversion narrative as a kind of published sermon. Later revisions reduced or erased traces of his earlier religious radicalism, and demonstrated his growing competence as minister and writer, but sometimes compromised authentically remembered spontaneous experience.
The Pilgrim’s Progress (1678)
Authors: Davies Michael
Published: August 2018

Focusing on Christian’s confrontation with Apollyon, this chapter provides an overview of John Bunyan’s first religious allegory and his most famous work of fiction: The Pilgrim’s Progress (originally published in 1678). It considers the enduring literary and imaginative power of The Pilgrim’s Progress by addressing Bunyan’s sophisticated control of popular fiction and the Bible, as well as of metaphor, allegory, and allegorical interpretation within its narrative form. It also places The Pilgrim’s Progress within some of its key theological and historical contexts, including the persecution of Nonconformists, such as Bunyan himself, who suffered throughout the Restoration for the sake of conscience and in the name of religious liberty for Protestant Dissenters.
The Holy War (1682)
Authors: Rosenfeld Nancy
Published: August 2018

By the early 1680s John Bunyan had achieved respect and popularity for his public preaching. As an author he attempted to build on the great success of The Pilgrim’s Progress, first with The Life and Death of Mr. Badman (1680) and then with The Holy War, which was published in 1682. Bunyan’s most ambitious and elaborate work of fiction took the form of an allegorical battle epic depicting the Christian scheme of salvation, the struggle of the human soul towards salvation, and contemporary and future events. This chapter discusses The Holy War in the context of the religious and literary works available to Bunyan, and as an impressive example of Bunyan’s skill in the creation of individuated literary characters.
The Prose Style of John Bunyan
Authors: Lund Mary Ann
Published: August 2018

This chapter examines Bunyan’s reputation as a prose stylist, his conceptions of style, and two important features of his writing—his use of dialogue and his control of pace—through an analysis of Grace Abounding to the Chief of Sinners (1666) and The Pilgrim’s Progress (1678; 1684). Although Bunyan characterizes his writing as ‘plain and simple’, this chapter argues that he deploys a range of linguistic registers and voices. It analyses his use of speech, showing how he uses dialogue not merely to aid characterization, but also to reveal individual spiritual states. For Bunyan, spiritual discernment requires developing correct responses to style, as Faithful learns in his encounter with Talkative. The chapter also explores the connection between Bunyan’s variations in narrative pace in the trials undergone by the pilgrims, showing how the experience of journeying is enacted in Bunyan’s command of his prose and in our experience of reading it.
Bunyan and the Word
Authors: Searle Alison
Published: August 2018

This chapter examines the changing nature of John Bunyan’s relationship with the Word of God as expressed in the Bible and the way it shaped his life and writing in a range of genres. Bunyan’s own experience of conversion, engendered as it was by his violent encounters with the Word of God both personally and communally, is considered first. This experience shaped Bunyan’s future readings of Scripture as an author and pastor. His biblical hermeneutic is then analysed. Finally, the ways in which Bunyan appropriated and was appropriated by the Bible in his life and works is explored by focusing on two themes that consistently characterize scriptural aspects both of his pastoral practice and of his entire oeuvre: marriage and pilgrimage.
‘Nor do thou go to work without my Key’
Authors: Hancock Maxine
Published: August 2018

A full reading of John Bunyan’s works demands that attention be paid not only to the central text, but also to the marginal notes. This chapter reviews the history of critical and editorial attention given to Bunyan’s marginal notes, and considers what is known regarding their import for Bunyan and for his seventeenth-century readers. In assessing the ongoing significance of the marginal notes for critical readings of Bunyan’s texts, this chapter also examines taxonomies of the functions and effects of these, as well as current theories of margination. Possible future directions for further work on the marginal notes are also considered as offering potentially enriching readings of Bunyan, in terms of the mimetic and dialogic aspects of the notes.
Bunyan and Empire
Authors: Brown Sylvia
Published: August 2018

This chapter examines the global circulation of Bunyan’s writings along the routes of empire. Translations and adaptations, distributed for the most part by missionaries, were recruited both for and against empire. The universalism imputed to The Pilgrim’s Progress (1678; 1684) facilitated its global distribution, seemingly overcoming differences as if by magic. Yet this same assumption of universalism also made the authority of Bunyan available to local uses, needs, and even resistance against colonialism and empire. The history of Bunyan’s global textual circulation suggests a mixed and problematic relation to imperial expansion and colonial ambitions. Finally, while the continuing global reach of Bunyan might be understood as a residue of the mobility of his texts both within and against empire, this has also generated a multitude of diverse local adaptations and appropriations which enable a refocusing away from the totalizing categories of nation and empire.
Bunyan and America
Authors: Rasmussen Joel D.S.
Published: August 2018

This chapter surveys the reception and appropriation of The Pilgrim’s Progress (1678; 1684) in American religious history and literary culture, arguing that, through a series of politically, theologically, and artistically motivated realignments, American adaptations of John Bunyan’s classic shaped key features of American Protestantism and of a distinctively American literary tradition. In the eighteenth century, The Pilgrim’s Progress was evoked to reconceive ‘progress’ along lines more commercial and technological than spiritual. In the nineteenth century, modernized spin-offs became important touchstones in the hotly contested debates over theological liberalism and conservatism. In the increasingly secular twentieth century, it was often either ‘emptied of religion’ and recast as ‘road literature’, or appropriated dialectically as a means for coming to terms with the perceived absurdity of the human condition. In sum, to quote Jean Bethke Elshtain, ‘the progress of Pilgrim’s Progress tells us a good bit about the American story’.
Introduction
Authors: Davies Michael
Published: August 2018

This chapter introduces The Oxford Handbook of John Bunyan. It reflects upon Bunyan’s ‘presence’ as a religious and historical figure and an author of major significance for literature, culture, and politics, both in the past and the present, in Britain and across the world. It contests the oft-alleged myth that Bunyan’s relevance has waned dramatically since the Second World War, being popular now, we are often told, only within academia and among evangelicals. By contrast, this chapter considers the living ‘resonance’ of Bunyan’s writings and of his legacy both in and for art, literature, and popular culture now in the broader terms of human rights and civil liberties, on the one hand, and a ‘memorial dynamics’ and the ‘portability’ of his works on the other. This chapter addresses the rationale behind this volume, explains its structure, summarizes its contents, and reflects too upon some future directions for ‘Bunyan studies’.
Bunyan’s Theology and Religious Context
Authors: Wallace Dewey D.
Published: August 2018

Familiarity with the theology of John Bunyan is important for the interpretation of his literary classics. That theology was Reformed, or Calvinist, focused on soteriology, and shaped by Bunyan’s search for faith and his experience in a Dissenting congregation on the borderline between Baptists and Independents. At its heart was an emphasis on the forgiveness of sins by a divine grace given without conditions, which Bunyan thought had been offered in the gospel to the worst of sinners, among whom he included himself. He articulated his theology through a scheme of covenants and an order of salvation that had already been developed as central components of Calvinism. The doctrine of predestination lurked in the background of his writings, but did not preclude his summons to conversion and a holy life. Bunyan laboured to bring well-grounded comfort and assurance of salvation to his readers and hearers.
Bunyan’s Partners in Print
Authors: Lynch Kathleen
Published: August 2018

Editor Charles Doe’s attempt to collect the works of John Bunyan is a landmark moment in a continuous history of print publication. This chapter explores the impact of book trade practices as they affected the circulation of Bunyan’s work and formed the basis of his reputation as an author. It focuses on two of Bunyan’s key publishers, Francis Smith and Nathaniel Ponder, as well as the engraver-publisher Robert White. In tracing the networks of association and community formation by which Bunyan’s texts circulated, and evaluating the risks imposed by the market and government regulation, the chapter brings material practices more fully into our accounts of literary history. In such a wider view, Bunyan’s discourse of religious confession is put in touch with discourses of truthful testimony, as in the courtroom trials of Smith and Ponder over seditious libel and property rights.
A Framework and Resources for Shared Decision Making: Opportunities for Improved Physical Therapy Outcomes
Authors: Moore Cindy L , Kaplan Sandra L
Published: August 2018

Shared decision making (SDM) is a collaborative approach between clinicians and patients, where the best available evidence is integrated with patients’ values and preferences for managing their health problems. Shared decision making may enhance patient-centered care and increase patients’ satisfaction, engagement, adherence, and ability to self-manage their conditions. Despite its potential benefits, SDM is underutilized by physical therapists, and frequent mismatches between patients’ and therapists’ rehabilitation goals have been reported. Physical therapists can use evidence-based strategies, tools, and techniques to address these problems. This paper presents a model for SDM and explains its association with improved patient outcomes and relevance to situations commonly encountered in physical therapy. It describes freely available resources, including health literacy universal precautions, teach-back, motivational interviewing, decision aids, and patient-reported outcome measures that can help physical therapists integrate SDM into their clinical practices. This paper also explains SDM facilitators and barriers, suggests a theoretical framework to address them, and highlights the need for SDM promotion within physical therapy practice, education, administration, and research.
Limited Stock Market Participation Among Renters and Homeowners
Authors: Vestman Roine
Published: August 2018

The stock market participation rate among homeowners is twice as high as among renters. This paper builds a life-cycle portfolio choice model with endogenous housing tenure choice. A stylized form of preference heterogeneity generates a substantial difference in participation rates. A majority of households have a large savings motive and choose to be homeowners and participate. A minority of households have a small savings motive and find it less worthwhile to participate. Fewer of these households become homeowners. Difference-in-difference regressions on panel data do not find evidence of a crowding-out effect of homeownership on participation, supporting the message that preference heterogeneity matters.

Received January 25, 2017; editorial decision March 21, 2018 by Editor Wei Jiang. Authors have furnished an Online Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Rifaximin in nonalcoholic fatty liver disease: hit multiple targets with a single shot
Authors: Abdel-Razik Ahmed , Mousa Nasser , Shabana Walaa , Refaey Mohamed , Elzehery Rasha , Elhelaly Rania , Zalata Khaled , Abdelsalam Mostafa , Eldeeb Ahmed A. , Awad Mahmoud , Elgamal Ayman , Attia Ahmed , El-Wakeel Niveen , Eldars Waleed
Published: August 2018

Background/Aims

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) may include increased insulin resistance, upregulation of proinflammatory cytokines, lipopolysaccharide, and BMI. Rifaximin is a minimally absorbable antibiotic that might act against a broad spectrum of gut bacteria. This study aimed to investigate the effects of rifaximin on NAFLD.

Patients and methods

Fifty participants with biopsy-proven nonalcoholic steatohepatitis (NASH) were registered in this multicentric, double-blind, randomized, placebo-controlled study. BMI, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, lipid profile, serum endotoxin, homeostatic model assessment, toll-like receptor-4, interleukin-10 (IL-10), IL-6, tumor necrosis factor-α, and cytokeratin-18 (CK-18) levels were evaluated at baseline and at 1, 3, and 6 months of rifaximin therapy (1100 mg/day).

Results

Patients were randomized into two groups (rifaximin group; n=25 and placebo group; n=25). After 6 months of rifaximin therapy, patients with NASH showed a significant reduction in homeostatic model assessment, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, endotoxin, toll-like receptor-4, IL-6, tumor necrosis factor-α, CK-18, and NAFLD-liver fat score (all P<0.05), but no changes in the lipid profile; moreover, there was a mild nonstatistically significant reduction of BMI. However, in the placebo group, there was no significant difference in these variables at baseline and after therapy.

Conclusion

Rifaximin therapy appears to be effective and safe in modifying NASH through reduction of serum endotoxin and improvement of insulin resistance, proinflammatory cytokines, CK-18, and NAFLD-liver fat score.
Evolutionarily developed connections compromised in schizophrenia
Authors: van den Heuvel Martijn P. , Scholtens Lianne H. , de Lange Siemon C. , Pijnenburg Rory , Cahn Wiepke , van Haren Neeltje E.M. , Sommer Iris , Li Longchuan , Preuss Todd , Rilling James K.
Published: August 2018

The genetic basis and uniquely human character of schizophrenia has led to the notion of human brain evolution to have resulted in vulnerability to the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparingin-vivoneuroimaging data from humans, chimpanzees and macaque monkeys. We find that evolutionary changes in human connectome organization overlap with the pattern of schizophrenia-related changes in brain connectivity, with connections evolutionary enhanced in the human brain showing significantly more involvement in schizophrenia pathology than connections shared between humans and non-human primates (effects shown in three independent patient-control datasets). Our findings suggest that the evolution of brain wiring in support of complex brain function in humans may have come at the cost of an increased vulnerability to brain dysfunction in disease.
deepMc: deep Matrix Completion for imputation of single cell RNA-seq data
Authors: Mongia Aanchal , Sengupta Debarka , Majumdar Angshul
Published: August 2018

Single cell RNA-seq has fueled discovery and innovation in medicine over the past few years and is useful for studying cellular responses at individual cell resolution. But, due to paucity of starting RNA, the data acquired is highly sparse. To address this, We propose a deep matrix factorization based method, deepMc, to impute missing values in gene-expression data. For the deep architecture of our approach, We draw our motivation from great success of deep learning in solving various Machine learning problems. In this work, We support our method with positive results on several evaluation metrics like clustering of cell populations, differential expression analysis and cell type separability.
Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries
Authors: Troja Weston , Owens Kathryn J. , Courtney Jennifer , Hinton Andrea C. , Hinton Robert B. , Cnota James F. , Jones Helen N.
Published: August 2018

Background

Birthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD.

Methods

Clinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Gene, analysis was performed using TopHat, R and MSigDB. Cluster analysis was performed using GoElite and Pathway analysis performed using PANTHERdb Overrepresentation Test. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups.

Results

Placental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi, and increased fibrin deposition in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Need to include RNA and IHC.

Conclusions

Despite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the
Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk
Authors: Nalls Mike A. , Blauwendraat Cornelis , Vallerga Costanza L. , Heilbron Karl , Bandres-Ciga Sara , Chang Diana , Tan Manuela , Kia Demis A. , Noyce Alastair J. , Xue Angli , Bras Jose , Young Emily , von Coelln Rainer , Simón-Sánchez Javier , Schulte Claudia , Sharma Manu , Krohn Lynne , Pihlstrom Lasse , Siitonen Ari , Iwaki Hirotaka , Leonard Hampton , Faghri Faraz , Raphael Gibbs J. , Hernandez Dena G. , Scholz Sonja W. , Botia Juan A. , Martinez Maria , Corvol Jean-Christophe , Lesage Suzanne , Jankovic Joseph , Shulman Lisa M. ,   The 23andMe Research Team,   System Genomics of Parkinson’s Disease (SGPD) Consortium, Sutherland Margaret , Tienari Pentti , Majamaa Kari , Toft Mathias , Andreassen Ole A. , Bangale Tushar , Brice Alexis , Yang Jian , Gan-Or Ziv , Gasser Thomas , Heutink Peter , Shulman Joshua M , Wood Nicolas , Hinds David A. , Hardy John A. , Morris Huw R , Gratten Jacob , Visscher Peter M. , Graham Robert R. , Singleton Andrew B. ,   for the International Parkinson’s Disease Genomics Consortium
Published: August 2018

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.
Homing and Egg Discrimination in the Western Slimy Salamander,Plethodon albagula(Caudata: Plethodontidae)
Authors: Jordan Robyn R. , Milanovich Joseph R. , Mccallum Malcolm L. , Trauth Stanley E.
Published: August 2018

In some species of vertebrates egg brooding is a costly form of parental care. Therefore, misdirection of parental care can significantly lower a female’s fitness. Because of the maternal investment and increased survivorship to offspring from egg guarding, a brooding female should home to her nest site after being displaced a short distance and discriminate between her own eggs and eggs from other females. In this study, we experimentally tested, in the field, alternative hypotheses concerning homing ability and egg discrimination in a population of nesting western slimy salamanders (Plethodon albagula). Fourteen brooding females were displaced 1 m to the left or right of their nest sites (determined randomly) for the homing experiment. Furthermore, brooding females (n = 13) were presented with their own clutches, which were displaced 50 cm to the left or right (determined randomly), and unfamiliar egg clutches at their original nest sites. The females were released at an equal distance from both egg clutches. After 24 hours, 12 displaced females (86%) had returned to their own nest sites and were brooding their egg clutches. Also, after 24 hours, nine test females had returned to their own nest sites and were brooding the unfamiliar egg clutches. No control or test females were present at the other new nest site locations. Therefore, we suggest that brooding femaleP. albagulado home to their nest sites and exhibit indirect egg discrimination.
Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer
Authors: Guo Charles C. , Majewski Tadeusz , Zhang Li , Yao Hui , Bondaruk Jolanta , Wang Yan , Zhang Shizhen , Wang Ziqiao , Lee June Goo , Lee Sangkyou , Cogdell David , Zhang Miao , Wei Peng , Grossman H. Barton , Kamat Ashish , Duplisea Jonathan James , Ferguson James Edward , Huang He , Dadhania Vipulkumar , Dinney Colin , Weinstein John N. , Baggerly Keith , McConkey David , Czerniak Bogdan
Published: August 2018

The sarcomatoid variant of urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARCs and 84 cases of conventional urothelial carcinomas (UCs), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape with enrichment ofTP53, RB1, and PIK3CAmutations. They were related to the basal molecular subtype of conventional UCs and could be divided into epithelial/basal and more clinically aggressive mesenchymal subsets based on TP63 and its target genes expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of cell cycle and EMT networks, and nearly half exhibited a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.
HSP-4/BiP expression in secretory cells is regulated by a lineage-dependent differentiation program and not by the unfolded protein response
Authors: Zha Ji , Alexander-Floyd Jasmine , Gidalevitz Tali
Published: August 2018

Differentiation of secretory cells leads to sharp increases in protein synthesis, challenging ER proteostasis. Anticipatory activation of the unfolded protein response (UPR) prepares cells for the onset of secretory function by expanding the ER size and folding capacity. How cells ensure that the repertoire of induced chaperones matches their post-differentiation folding needs is not well understood. We find that during differentiation of stem-like seam cells, a typical UPR target, theC. elegansBiP homologue HSP-4, is selectively induced in alae-secreting daughter cells, but is repressed in hypodermal daughter cells. Surprisingly, this lineage-dependent induction bypasses the requirement for UPR signaling, and instead is controlled by a specific developmental program. The repression of HSP-4 in hypodermal-fated cells requires a transcriptional regulator BLMP-1/BLIMP1, involved in differentiation of mammalian secretory cells. The HSP-4 induction is anticipatory, and is required for the integrity of secreted alae. Thus, differentiation programs can directly control a broad-specificity chaperone that is normally stress-dependent, to ensure the integrity of secreted proteins.
A nanotube-mediated path to protocell formation
Authors: Köksal Elif Senem , Liese Susanne , Kantarci Ilayda , Olsson Ragni , Carlson Andreas , Gözen Irep
Published: August 2018

Cellular compartments are membrane-enclosed, spatially distinct microenvironments which confine and protect biochemical reactions in the biological cell. On the early Earth, the autonomous formation of compartments is thought to have led to the encapsulation of nucleotides, thereby satisfying a starting condition for the emergence of life. Recently, surfaces have come into focus as potential platforms for the self-assembly of prebiotic compartments, as significantly enhanced vesicle formation was reported in the presence of solid interfaces. The detailed mechanism of such formation at the mesoscale is still under discussion. We report here on the spontaneous transformation of solid surface-adhered lipid deposits to unilamellar membrane compartments through a straightforward sequence of topological changes, proceeding via a network of interconnected lipid nanotubes. We show that this transformation is entirely driven by surface-free energy minimization and does not require hydrolysis of organic molecules, or external stimuli such as electrical currents or mechanical agitation. The vesicular structures take up and encapsulate their external environment during formation, and can subsequently separate and migrate upon exposure to hydrodynamic flow. This may link, for the first time, the self-directed transition from weakly organized bioamphiphile assemblies on solid surfaces to protocells with secluded internal contents.

Significance

The nature of the physical and chemical mechanisms behind the formation, growth and division of the earliest protocells is among the key questions concerning the origin of life. Establishing a simple pathway for the assembly of protocell structures from the primordial soup is a particular challenge. Emerging evidence supporting the assumption that solid surfaces have a governing role in protocell formation has recently expanded the scope, and created new inspiration for investigation. By presenting a physical path from self-assembled amphiphile-based membranes on solid surfaces to spherical single-membrane compartments via a consistent sequence of transformations, solely driven by the materials properties of the interfaces, a direct link between the presence of functional biomolecules and the development of protocells can be established.
Selective pressures on human cancer genes along the evolution of mammals
Authors: Vicens Alberto , Posada David
Published: August 2018

Cancer is a disease of the genome caused by somatic mutation and subsequent clonal selection. Several genes associated to cancer in humans, hereafter cancer genes, also show evidence of (germline) positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for statistically significant signatures of positive selection using dN/dS models in a list of 430 cancer genes. Among these, we identified 63 genes under putative positive selection in mammals, which are significantly enriched in processes like crosslinking DNA repair. We also found evidence of a higher incidence of positive selection in cancer genes bearing germline mutations, like BRCA2, where positively selected residues are physically linked with known pathogenic variants, suggesting a potential association between germline positive selection and risk of hereditary cancer. Overall, our results suggest that genes associated with hereditary cancer have less selective constraints than genes related to sporadic cancer. Also, that the adaptive evolution of human cancer genes in mammals has been most likely driven by adaptive changes in important traits not directly related to cancer.
Evidence for phospholipid export from the gram-negative inner membrane: time to rethink the Mla pathway?
Authors: Hughes Gareth W. , Hall Stephen C. L. , Laxton Claire S. , Sridhar Pooja , Mahadi Amirul H. , Hatton Caitlin , Piggot Thomas J. , Jamshad Mohammed , Spana Vaclav , Ian Cadby T. , Harding Christopher , Isom Georgia L. , Bryant Jack , Parr Rebecca J. , Yakub Yasin , Jeeves Mark , Huber Damon , Ian Henderson R. , Clifton Luke A. , Andrew Lovering L. , Knowles Timothy J.
Published: August 2018

The Mla pathway is believed to be involved in maintaining the asymmetrical Gram-negative outer membrane via retrograde phospholipid transport. The pathway is composed of 3 components: the outer membrane MlaA-OmpC/F complex, a soluble periplasmic protein, MlaC, and the inner membrane ATPase, MlaFEDB complex. Here we solve the crystal structure of MlaC in its phospholipid free closed apo conformation, revealing a novel pivoting β-sheet mechanism which functions to open and close the phospholipid-binding pocket. Using the apo form of MlaC we provide evidence that the Mla pathway functions in an anterograde rather than a retrograde direction by showing the inner membrane MlaFEDB machinery exports phospholipids and transfers them to MlaC in the periplasm. We confirm that the lipid export process occurs through the MlaD component of the MlaFEDB complex. This lipid export process is shown to be independent of ATP. Our data provides, for the first time, evidence of an apparatus for lipid export to the outer membrane.
Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities
Authors: Stewart Michelle , Lau Petrina , Banks Gareth , Bains Rasneer Sonia , Castroflorio Enrico , Oliver Peter L. , Dixon Christine L. , Kruer Michael C. , Kullmann Dimitri M. , Acevedo-Arozena Abraham , Wells Sara E. , Corrochano Silvia , Nolan Patrick M.
Published: August 2018

Summary statement

In this study, we show that the loss of the epilepsy-related gene Frrs1l in mice causes a dramatic reduction in AMPA receptor levels at the synapse. This change elicits severe motor and coordination disabilities, hyperactivity, cognitive defects, behavioural seizures and abnormal electroencephalographic (EEG) patterns.

Loss of function mutations in the human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies have implicated FRRS1L in AMPA receptor biogenesis and assembly, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l-/- mice were hyperactive irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic recordings also revealed abnormal EEG in Frrs1l-/- mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l-/- mice, while the general levels of several other synaptic components remained unchanged with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in glycosylation deficits in GLUA2 and GLUA4 AMPA receptor proteins, leading to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.