bluuebunny/crossref_metadata_2025 huggingface dataset:
Pragmatics and the Lexicon
Authors: Horn Laurence
Published: August 2014

Since Paul and Zipf, it has become evident that lexical choice and meaning change are largely guided by pragmatic principles. Two central interacting principles are, first, the least-effort tendency to reduce expression and, second, the communicative requirements on sufficiency of information. Descendants of this opposition include Grice’s bipartite Maxim of Quantity (‘Make your contribution as informative as/no more informative than is required’) grounded within a general theory of rationality and cooperation, the Q and R Principles (essentially ‘Say enough’/‘Don’t say too much’), and the interplay of effort and effect within Relevance Theory. This chapter motivates a (Q-based) constraint on lexicalization, surveys the role of the R principle in motivating the Division of Pragmatic Labour, syntagmatic reduction, narrowing of meaning, euphemism, and negative strengthening, and provides pragmatic motivation for the lexical clone, un-noun, and un-verb constructions, and for the complementary Avoid Synonymy and Avoid Homonymy principles.
Hume and the Contemporary “Common Sense” Critique of Hume
Authors: Falkenstein Lorne
Published: August 2014

This paper examines the principal objections that Hume’s Scots contemporaries, George Campbell, James Beattie, and Thomas Reid raised against his views of testimony, belief, and the “theory of ideas.” In opposition to Kant’s claim that “Reid, Oswald, and Beattie” had “appealed to common sense as an oracle when insight and research [failed them]” and had “[taken] for granted what [Hume] meant to call into doubt while emphatically, and often with great indignation, demonstrating what he had never thought to question” it is shown that, in each case, Hume’s critics understood him correctly and raised serious objections. But it is also shown that Hume’s work contains all the materials necessary to mount an effective response to their objections.
Hume on Evil
Authors: Newlands Samuel
Published: August 2014

This paper focuses on Hume’s discussions of evil, with an eye toward both contemporary disputes in philosophy of religion and Hume’s own eighteenth-century context. Following preliminary remarks about the texts and context, the second section explores the wide variety of problems of evil found in Hume’s writings, arguing that this multifaceted presentation is one of Hume’s greatest contributions to contemporary discussions of evil. In the third section, the focus shifts to the unfolding discussion of evil in Dialogues X–XI, offering a close, critical reading of the exchanges between Philo and Cleanthes. The final section consists of a critical evaluation of Hume’s main claims concerning God and evil, ending with an overview of Hume’s enduring legacy on this topic.
Reason, Belief, and the Passions
Authors: Owen David
Published: August 2014

Hume said that reason alone cannot motivate and that passions are required to produce volitions and actions. It is argued that the widely, though not universally, held “Humean” view of motivation—that beliefs require desires to motivate actions—does not accurately reflect Hume’s own view. The author argues here that beliefs, especially beliefs about pleasure, do motivate. But beliefs are produced by probable reasoning. And this seems to imply that reason alone does motivate, i.e., produces, via beliefs, volitions and actions. It is argued that the seeming inconsistency that appears to result is only apparent. An interpretation of what Hume means by “reason alone” is provided.
Hume’s Philosophical Economics
Authors: Sakamoto Tatsuya
Published: August 2014

Hume’s economic essays were part of his early project of politics as one of the principal departments of the Science of Man, a project realized, first, by the morals expounded in Book 3 of the Treatise; second, by the politics and criticism in Essays Moral and Political; and third, by economic and political essays in the Political Discourses. The author sheds new light on the way in which Hume’s economic theory was developed as an integral part of his grand philosophical project, one based on the theory of causal reasoning that served Hume’s theorizing throughout his social science in general and his economics in particular. A profound connection is shown between Hume’s philosophy and economics, mainly from a methodological point of view, by highlighting his theory of causation. The strictly philosophical nature and origin of Hume’s “economics” demonstrates the significant difference between his economic writings and those of his contemporaries.
Hume’s Natural History of Religion
Authors: Yandell Keith E.
Published: August 2014

Hume’s Dialogues Concerning Natural Religion, Dialogues 1–11 discuss religion’s foundation in human reason. Dialogue 12, in which Philo. the relentless opponent of pro-theistic arguments, makes his “confession” that he embraces natural religion; namely, the view that the cause or causes of order in nature bear some remote analogy to human intelligence. Hume’s Natural History of Religion, although published earlier than the posthumous Dialogues, is, in effect, a second volume to them. It presents a complex naturalistic explanation of religion’s origin in human nature, providing a sophisticated (and controversial) account of religion’s origin that is also a critique of religious belief. The core of this critique is an argument that theistic belief cannot be rendered so as to significantly differ from an atheism that grants that natural order has some cause or other.
Hume on Space and Time
Authors: Baxter Donald L.M.
Published: August 2014

For Hume, the ideas of space and of time are each a general idea of some indivisible objects arranged in a certain manner with additional qualities that make them conceivable to the mind. He argues that the structures of these ideas reflect the structures of space and time. Thus, space and time are not infinitely divisible, and there cannot be empty space nor time without succession. Hume’s idiosyncratic theory can be seen to be reasonable if one pays careful attention to the fact that Hume, in accordance with his skepticism, is concerned only to give vent to views about space and time as they appear in experience. The chapter focuses on explicating Hume’s central arguments rather than trying to give a comprehensive treatment.
Hume and Proofs for the Existence of God
Authors: Bell Martin
Published: August 2014

This chapter is about Hume’s critiques of the cosmological, ontological, and design arguments for the existence of God, as proposed by Samuel Clarke and other Newtonian theologians. Clarke regarded the cosmological argument (in a form that incorporates the ontological argument) as essential to prove the uniqueness, eternity, infinity, and omnipresence of God and the design argument as essential to prove the wisdom and foresight of God. The criticisms Hume makes all depend on his empiricist theory of ideas and his revolutionary theories of causation and causal reasoning. Most of the chapter discusses these themes. The concluding section draws attention to recent research that shows two things. One is how central to Hume’s whole philosophical enterprise is his rejection of theological ideas and doctrines. The other is how this relates to his rejection of certain parts of Newtonian metaphysics.
Individual Consequences of Job Loss and Unemployment
Authors: Paul Karsten I. , Hassel Alice , Moser Klaus
Published: August 2014

Scholars from several different fields have studied the individual consequences of job loss and unemployment since the beginning of the twentieth century. This chapter provides a review of some important results of this research with special emphasis on the effects of unemployment on mental health. Among the topics reviewed are the size and practical relevance of these effects and the question of causality (i.e., does job loss really cause distress or are people with distress symptoms more likely to lose their jobs and remain unemployed for a longer time?) Results of moderator variables are also reviewed, as well as those concerning coping mechanisms. Then theories concerning the question of why unemployment impairs mental health (mediating mechanisms) are described, along with empirical results. Finally, some selected research findings for other outcome dimensions, ranging from physical health to political attitudes, are reported. The chapter ends with a discussion of the practical consequences of the reviewed research findings and the identification of research gaps.
Assimilation in the Past and Present
Authors: Alba Richard
Published: August 2014

The notion of assimilation by immigrant groups remains beset by conceptual confusion. An examination of the way that assimilation developed in the American past, especially in the period after World War II, provides a way of cutting through the conceptual fog. Key features of historical assimilation are captured by the definition of the concept in neo-assimilation theory. However, debate over the present-day role of mainstream assimilation has been renewed by the advent of segmented assimilation. Both theories can point to evidence about the second generations issuing from contemporary immigrant groups to support their claims. A mixed picture is also found in the fundamental economic and demographic trends that are prognostic about assimilation.
Whiteness and Race
Authors: Roediger David R.
Published: August 2014

This article situates the growing literature on European immigration to the United States and white racial identity in the larger body of research on immigration history and in inspirations from literature and social theory. It places the new work, debates among those producing it, and critical responses to it within historiography and recent political debates. Differences over the utility of the idea that immigrants “became white” in the United States are especially emphasized, as are the ways that class, law, and gender intersect with race. Suggestions for further research are offered in conclusion.
Immigration, Medical Regulation, and Eugenics
Authors: Kline Wendy
Published: August 2014

In the late nineteenth century, as fears of contamination latched onto eugenic anxieties about racial degeneration, the medical regulation of foreigners attempting to enter the United States became particularly intense. Ideas about contagion and degeneration characterized the medical regulation of immigrants around the turn of the twentieth century, and many of these ideas remain with us today.
Panic Attacks During Pregnancy and the Postpartum Period
Authors: Beck Cheryl Tatano
Published: August 2014

Panic attacks during pregnancy and the postpartum period are associated with substantial distress and impairment in women. Although perhaps the mostly likely course of perinatal panic disorder (PPD) is that women experience no change in symptoms, there appears to be a substantial minority whose symptoms improve during pregnancy but worsen in the postpartum period. Preliminary research suggests that panic disorder is associated with adverse child outcomes; thus, antenatal screening and diagnosis of panic disorder need to become routine obstetric practice so that treatment can be initiated when indicated. Treatment for PPD often requires a combined approach of pharmacotherapeutics and psychotherapy, such as antidepressants and cognitive behavioral therapy. Much additional research, both qualitative and quantitative, is necessary to target rates of comorbidity in women with PPD, risk factors for PPD, consequences of PPD, and the assessment and treatment of PPD.
Prevention of Postpartum Psychopathology
Authors: Tzilos Golfo , Davis Kristina , Zlotnick Caron
Published: August 2014

Approximately 26% of postpartum women meet diagnostic criteria for a psychiatric disorder. Untreated psychopathology in the postpartum period is associated with a range of adverse outcomes for both infant and mother. Fortunately, the perinatal period provides an opportune time to intervene with and prevent postpartum psychopathology. Women have increased contact with health care providers during this time, providing an avenue through which access to prevention can be improved. Furthermore, with increased knowledge to identify high-risk women, preventive interventions can be delivered to assist both the woman and infant. Preventive efforts for postpartum psychopathology are aimed at modifying risk factors or protective factors to prevent the psychiatric disorder and primarily use three distinct approaches: universal, selective, and indicated. This chapter provides a review of the empirical research in the prevention of postpartum psychopathologies including postpartum depression, anxiety, bipolar disorder, psychosis, and addictions (tobacco, alcohol, and illicit drugs).
Identity in Emerging Adulthood
Authors: Schwartz Seth J. , Zamboanga Byron L. , Luyckx Koen , Meca Alan , Ritchie Rachel
Published: August 2014

This chapter presents a review of identity status-based theory and research with adolescents and emerging adults, with some coverage of related approaches such as narrative identity and identity style. In the first section, the authors review Erikson’s theory of identity and early identity status research examining differences in personality and cognitive variables across statuses. They then review two contemporary identity models that extend identity status theory and explicitly frame identity development as a dynamic and iterative process. The authors also review work that has focused on specific domains of identity. The second section of the chapter discusses mental and physical health correlates of identity processes and statuses. The chapter concludes with recommendations for future identity research with adolescent and emerging-adult populations.
The Challenge of Romantic Relationships in Emerging Adulthood
Authors: Shulman Shmuel , Connolly Jennifer
Published: August 2014

Whereas theories of romantic stage development suggest that youth in the period of emerging adulthood are fully capable of commitment to an intimate romantic relationship, recent research suggests that the relationships of many young people are quite different. Marriage and other forms of deep commitment are delayed while many youth engage in short-term casual encounters or in noncommitted relationships. This chapter suggests that these data pose a challenge to stage theories, one that can be reconciled by considering the developmental life tasks that emerging adults must simultaneously resolve. The authors propose a transitional emerging adult romantic stage, coordinating romance and life plans, in which young people strive to integrate career paths and life plans with those of a romantic partner. Resolution of this stage provides the grounding for long-term commitment to a life partner. This proposal is discussed within the perspective of life cycle and evolutionary life history theories.
Negotiating Freedom and Control in Composition
Authors: Feisst Sabine
Published: August 2014

This chapter discusses the many meanings of improvisation and free improvisation in Western classical music from 1950 to 1980 and examines criteria for improvisation, composition, and performance. It investigates concepts related to improvisation such as indeterminacy, chance, aleatory, open form, minimal music, and experimental music. Discussion focuses on the terminology, ideas, and selected works of Anthony Braxton, André Boucourechliev, Pierre Boulez, John Cage, Cornelius Cardew, Alvin Curran, Franco Evangelisti, Vinko Globokar, Roman Haubenstock-Ramati, Joëlle Léandre, Witold Lutosławski, Pauline Oliveros, Terry Riley, Karlheinz Stockhausen, Richard Teitelbaum, Frances-Marie Uitti, La Monte Young, and Pamela Z. Finally, it considers the role of composers and performers works involving improvisation, the improvisers’ relationship to the audience, and role of listeners in performances of improvised music.
The Role and Ramifications of the Media’s Reporting on Concussions
Authors: Carone Dominic A.
Published: August 2014

The media has become one of the main sources of information on sports concussion for the general public and health care providers. The widespread proliferation of this information carries positive and negative consequences that are reviewed here, along with case examples. Given the power that the media has to positively and negatively influence societal change, public perception, and clinical care, the media must pay special attention as to how this information is presented. Suggestions on ways to improve media coverage of sports concussions are discussed.
Moderate to Severe Traumatic Brain Injury in Sports
Authors: Cantu Robert C. , Cantu Robert V.
Published: August 2014

Traumatic brain injury in sports encompasses a spectrum including injuries such as concussion, skull fracture, intracranial hemorrhage, malignant brain edema syndrome, and axonal shear. Knowledge of these injuries and their signs and symptoms is important for medical personnel covering a sporting contest or practice. The authors discuss each of these injuries, how they typically occur, and what the initial treatment entails.
Acute Evaluation and Management of Sport-Related Concussion
Authors: Broglio Steven P.
Published: August 2014

The acute evaluation and management of concussion are among the most complex and challenging injuries medical practitioners face. The variability in clinical presentation necessitates a systematic approach to the injury evaluation. The evaluation should include a thorough injury history and clinical examination that is supported by objective measures of mental status and motor control. The integration of all information should be used in making the clinical diagnosis.
Film Music and Neo-Riemannian Theory
Authors: Lehman Frank
Published: August 2014

Triadic chromaticism is a feature of much dramatic film scoring, a repertoire that has previously received little in the way of sustained analytic attention from music theorists. Neo-Riemannian techniques, while limited in application in most previous studies to nineteenth-century music, are eminently suited to exploring this vast musical landscape. Using passages of characteristically “nonfunctional” tonal logic from scores by Hollywood’s leading composers, this article demonstrates the relevance of transformational parameters to the investigation of cinematic musical structure and expression. The interpretive usefulness of neo-Riemannian harmonic combinatoriality and its sensitivity to voice-leading is highlighted with intuitive but hermeneutically revealing analyses of music from John Williams, Bernard Herrmann, and Howard Shore. The interaction of diatonic functional and chromatic idioms is broached with examples from Alfred Newman, as is the notion of “tonal agnosticism,” which underlies much neo-Riemannian scholarship. Two larger analyses, of Alan Silvestri’s Back to the Future and Erich Wolfgang Korngold’s The Sea Hawk, illustrate the power and limitations of symmetry—too often an uncritically assumed desideratum for transformational approaches—for organizing film time. In light of these analyses, the wider prospects for future research in cinematic transformational analysis are considered.
Youth Justice in Israel
Authors: Ajzenstadt Mimi
Published: August 2014

Policies in Israel retain the traditional view that juvenile delinquents should be treated and rehabilitated. These policies are driven by changing rationalities, norms, and values, which are socially and culturally contextualized. There has been an overarching ideology characterizing the sociolegal response to juvenile delinquency in Israel over time, with a welfare orientation that has been modified according to ideological influences and practical considerations. At the same time, informal, needs-oriented, and child-centered principles have continued to be adopted. This essay provides a review of the organization and operation of the system with regard to juvenile delinquency in Israel. It locates policy developments taking place in Israel within a wider sociopolitical context.
Lay Adjudication around the World
Authors: Malsch Marijke
Published: August 2014

Lay adjudication is a widely discussed topic in the present-day debate on legal systems. Around the world, a large variety of types of lay adjudication exists. Almost all countries make use of lay people as judges, and many of them have several forms of lay adjudication. This article discusses three models of lay adjudication: the jury, mixed panels, and experts as judges. It elaborates on the issues of legitimacy and the question as to whether lay participation increases various aspects of democracy within the legal system. Advantages and drawbacks are discussed. The article ends with a tentative prospective into the future.
The Role of Muslims and the Holocaust
Authors: Afridi Mehnaz M.
Published: August 2014

This article explores the role that Muslims played during the Holocaust. It explores historical and religious anti-Semitism in the Arab world and the consequences that led to the denial and relativism of the Holocaust. The article contends that Muslims were also rescuers and victims with Jews in Arab countries under the Vichy government and shows how entrenched the colonial forces were in Arab/Muslim lands during World War II. The conclusion of the article points to literature and scholarly works that might bridge an understanding between Jews and Muslims through Holocaust and postcolonial understanding.
Molecular Genetic Analysis of Cucumber mosaic virus Populations Infecting Pepper Suggests Unique Patterns of Evolution in Korea
Authors: Kim Mi-Kyeong , Seo Jang-Kyun , Kwak Hae-Ryun , Kim Jeong-Soo , Kim Kook-Hyung , Cha Byeong-Jin , Choi Hong-Soo
Published: August 2014

Studying genetic structure and diversity of viruses is important to understand the evolutionary mechanisms that generate and maintain variations in viral populations. Cucumber mosaic virus (CMV) is endemic in most pepper fields in Korea. Currently, no effective methods for control of CMV are available due to many environmental and biological factors such as the extensive evolutionary capacity of CMV. Thus, analyzing the genetic structure of CMV populations may facilitate the development of strategies for the control of CMV. In this study, 252 pepper (Capsicum annuum) samples showing virus symptoms were collected by field surveys performed throughout Korea in 2007. Reverse-transcription polymerase chain reaction analyses revealed that, in total, 165 collected samples were infected with CMV. Forty-five CMV isolates were randomly selected within each regional subpopulation and analyzed by full-genome sequencing. Analyses of genetic diversity showed that the 2b gene of CMV is under weaker purifying selection than the other genes. Based on the phylogenetic analysis of RNA1, the CMV isolates from pepper were divided into three clusters in subgroup I. Our full-genome sequence-based molecular analyses of the CMV Korean population suggest that the subpopulations of CMV have been geographically localized in pepper fields in Korea.
Contraction or expansion of the Moon's crust during magma ocean freezing?
Authors: Elkins-Tanton Linda T. , Bercovici David
Published: August 2014

The lack of contraction features on the Moon has been used to argue that the Moon underwent limited secular cooling, and thus had a relatively cool initial state. A cool early state in turn limits the depth of the lunar magma ocean. Recent GRAIL gravity measurements, however, suggest that dikes were emplaced in the lower crust, requiring global lunar expansion. Starting from the magma ocean state, we show that solidification of the lunar magma ocean would most likely result in expansion of the young lunar crust, and that viscous relaxation of the crust would prevent early tectonic features of contraction or expansion from being recorded permanently. The most likely process for creating the expansion recorded by the dikes is melting during cumulate overturn of the newly solidified lunar mantle.
Rb-Sr, Sm-Nd and Lu-Hf isotope systematics of the lunar Mg-suite: the age of the lunar crust and its relation to the time of Moon formation
Authors: Carlson Richard W. , Borg Lars E. , Gaffney Amy M. , Boyet Maud
Published: August 2014

New Rb-Sr,
146,147
Sm-
142,143
Nd and Lu-Hf isotopic analyses of Mg-suite lunar crustal rocks 67667, 76335, 77215 and 78238, including an internal isochron for norite 77215, were undertaken to better define the time and duration of lunar crust formation and the history of the source materials of the Mg-suite. Isochron ages determined in this study for 77215 are: Rb-Sr=4450±270 Ma,
147
Sm-
143
Nd=4283±23 Ma and Lu-Hf=4421±68 Ma. The data define an initial
146
Sm/
144
Sm ratio of 0.00193±0.00092 corresponding to ages between 4348 and 4413 Ma depending on the half-life and initial abundance used for
146
Sm. The initial Nd and Hf isotopic compositions of all samples indicate a source region with slight enrichment in the incompatible elements in accord with previous suggestions that the Mg-suite crustal rocks contain a component of KREEP. The Sm/Nd—
142
Nd/
144
Nd correlation shown by both ferroan anorthosite and Mg-suite rocks is coincident with the trend defined by mare and KREEP basalts, the slope of which corresponds to ages between 4.35 and 4.45 Ga. These data, along with similar ages for various early Earth differentiation events, are in accord with the model of lunar formation via giant impact into Earth at
ca
4.4 Ga.
The giant impact hypothesis: past, present (and future?)
Authors: Hartmann William K.
Published: August 2014

At the request of editors, this paper offers a historical review of early work on the giant impact hypothesis, as well as comments on new data. The author hereby claims (whether believable or not) that his interest is to move towards a correct model of lunar origin, not to defend a possibly incorrect idea, just because of being a co-author of a relevant early paper. Nonetheless, the 1974 giant impact hypothesis appears still to be viable.
On the evolution of the protolunar disc
Authors: Ward William R.
Published: August 2014

The structure and viscous evolution of a post-impact, protolunar disc is examined. The equations for a silicate disc in two-phase (vapour–liquid) equilibrium are employed to derive an analytical solution to vertical structure. Both a vertically mixed phase disc and a stratified disc, where a magma layer exists in the mid-plane surrounded by a vapour reservoir, are considered. The former largely reproduces the low gas mass fraction,
x
≪1, profiles of the disc described in earlier literature that proposed that the disc would hover on the brink of gravitational instability. In the latter, the vapour layer has
x
∼1 and is generally gravitationally stable, while the magma layer is vigorously unstable. The viscous evolution of the stratified model is then explored. Initially, the disc quickly settles to a quasi-steady state with a vapour reservoir containing the majority of the disc mass. The magma layer viscously spreads on a time scale of approximately 3–4 years, during which vapour continuously condenses into droplets that settle to the mid-plane, maintaining the magma surface density in spite of disc spreading. Material flowing inwards is accreted by the Earth; material flowing outwards past the Roche boundary can become incorporated into accreting moonlets. This evolution persists until the vapour reservoir is depleted in approximately 50–100 years, depending on its initial mass.
Crystal structure of 2-(3,4-dimethoxyphenyl)-3-hydroxy-4H-chromen-4-one
Authors: Yoo Jin Sil , Lim Yoongho , Koh Dongsoo
Published: August 2014

In the title compound, C17H14O5, the dimethoxy-substituted benzene ring is twisted relative to the 4H-chromenon skeleton (r.m.s. deviation = 0.015 Å) by 5.2 (4)°. The C atoms of the methoxy groups lie close to the plane of their attached benzene ring [deviations = 0.036 (3) and 0.290 (3)Å for themetaandparasubstituents, respectively]. An intramolecular O—H...O hydrogen bond closes anS(5) ring. In the cystal, inversion dimers linked by pairs of O—H...O hydrogen bonds generateR22(10) loops and C—H...O interactions connect the dimers into [010] chains.
Degree of host susceptibility in the initial disease outbreak influences subsequent epidemic spread
Authors: Severns Paul M. , Estep Laura K. , Sackett Kathryn E. , Mundt Christopher C.
Published: August 2014

Disease epidemics typically begin as an outbreak of a relatively small, spatially explicit population of infected individuals (focus), in which disease prevalence increases and rapidly spreads into the uninfected, at‐risk population. Studies of epidemic spread typically address factors influencing disease spread through the at‐risk population, but the initial outbreak may strongly influence spread of the subsequent epidemic.

We initiated wheat stripe rust Puccinia striiformis f. sp. tritici epidemics to assess the influence of the focus on final disease prevalence when the degree of disease susceptibility differed between the at‐risk and focus populations.

When the focus/at‐risk plantings consisted of partially genetic resistant and susceptible cultivars, final disease prevalence was statistically indistinguishable from epidemics produced by the focus cultivar in monoculture. In these experimental epidemics, disease prevalence was not influenced by the transition into an at‐risk population that differed in disease susceptibility. Instead, the focus appeared to exert a dominant influence on the subsequent epidemic.

Final disease prevalence was not consistently attributable to either the focus or the at‐risk population when focus/at‐risk populations were planted in a factorial set‐up with a mixture (c. 28% susceptible and 72% resistant) and susceptible individuals. In these experimental epidemics, spatial heterogeneity in disease susceptibility within the at‐risk population appeared to counter the dominant influence of the focus.

Cessation of spore production from the focus (through fungicide/glyphosate application) after 1·3 generations of stripe rust spread did not reduce final disease prevalence, indicating that the focus influence on disease spread is established early in the epidemic.

Synthesis and applications. Our experiments indicated that outbreak conditions can be highly influential on epidemic spread, even when disease resistance in the at‐risk population is greater than that of the focus. Disease control treatments administered shortly after the initial outbreak within the focus may either prevent an epidemic from occurring or reduce its severity.
Comparative studies using the Morris water maze to assess spatial memory deficits in two transgenic mouse models of Alzheimer's disease
Authors: Edwards Stephen R , Hamlin Adam S , Marks Nicola , Coulson Elizabeth J , Smith Maree T
Published: August 2014

Evaluation of the efficacy of novel therapeutics for potential treatment of Alzheimer's disease (AD) requires an animal model that develops age‐related cognitive deficits reproducibly between independent groups of investigators. Herein we assessed comparative temporal changes in spatial memory function in two commercially available transgenic mouse models of AD using the Morris water maze (MWM), incorporating both visible and hidden platform training. Individual cohorts of cDNA‐based ‘line 85’‐derived double‐transgenic mice coexpressing the ‘Swedish’ mutation of amyloid precursor protein (APPSwe) and the presenillin 1 (PS1) ‘dE9’ mutation were assessed in the MWM at mean ages of 3.6, 9.3 and 14.8 months. We found significant deficits in spatial memory retention in APPSwe/PS1dE9 mice aged 3.6 months and robust deficits in spatial memory acquisition and retention in APPSwe/PS1dE9 mice aged 9.3 months, with a further significant decline by age 14.8 months. β‐Amyloid deposits were present in brain sections by 7.25 months of age. In contrast, MWM studies with individual cohorts (aged 4–21 months) of single‐transgenic genomic‐based APPSwe mice expressing APPSwe on a yeast artificial chromosomal (YAC) construct showed no significant deficits in spatial memory acquisition until 21 months of age. There were no significant deficits in spatial memory retention up to 21 months of age and β‐amyloid deposits were not present in brain sections up to 24 months of age. These data, generated using comprehensive study designs, show that APPSwe/PS1dE9 but not APPSwe YAC mice appear to provide a suitably robust model of AD for efficacy assessment of novel AD treatments in development.
KCNJ11 E23K variant is associated with the therapeutic effect of sulphonylureas in Chinese type 2 diabetic patients
Authors: Li Qing , Chen Miao , Zhang Rong , Jiang Feng , Wang Jie , Zhou Jian , Bao Yuqian , Hu Cheng , Jia Weiping
Published: August 2014

The aim of the present study was to investigate the effect of the E23K variant of the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene on gliclazide modified release (MR) treatment in newly diagnosed patients with type 2 diabetes mellitus (T2DM). A total of 108 diabetic patients with no history of antidiabetic medication was treated with gliclazide MR for 16 weeks and underwent follow up at Weeks 2, 4, 8, 12 and 16. All patients were genotyped for KCNJ11 E23K (rs5219). At baseline, patients with the KK genotype had higher blood glucose and lower serum insulin levels after oral glucose administration than patients with the EE and EK genotypes (P < 0.05 for all). During treatment, individuals with the KK genotype had lower fasting glucose levels and were more likely to attain the target fasting glucose level (Plog rank = 0.028) than E allele carriers. Patients with the KK genotype had larger augmentations in changes (Δ) in acute insulin response (P = 0.049) and Δ body mass index (P = 0.003). Moreover, patients with the EK genotype had a lower variance in changes in fasting insulin levels (P = 0.049) and homeostasis model assessment of β‐cell function (P = 0.021) than those with the KK genotype. The findings of the present study suggest that the KCNJ11 E23K variant is associated with a greater effect of sulphonylurea treatment in newly diagnosed Chinese patients with T2DM.
MicroRNAs differentially regulated in cardiac and skeletal muscle in health and disease: Potential drug targets?
Authors: Winbanks Catherine E , Ooi Jenny YY , Nguyen Sally S , McMullen Julie R , Bernardo Bianca C
Published: August 2014

The identification of non‐coding RNA species, previously thought of as ‘junk’ DNA, adds a new dimension of complexity to the regulation of DNA, RNA and protein. MicroRNAs are short non‐coding RNA species that control gene expression, are dysregulated in settings of cardiac and skeletal muscle disease and have emerged as promising therapeutic targets. MicroRNAs specifically enriched in cardiac and skeletal muscle are called myomiRs and play an important role in cardiac pathology and skeletal muscle biology. Moreover, microRNA profiles are altered in response to exercise and disease; thus, their potential as therapeutic drug targets is being widely explored. In the cardiovascular field, therapeutic inhibition of microRNAs has been shown to be effective in improving cardiac outcome in preclinical cardiac disease models. MicroRNAs that promote skeletal muscle regeneration are attractive therapeutic targets in muscle wasting conditions where regenerative capacity is compromised.
Expression of domains for protein–protein interaction of nucleotide excision repair proteins modifies cancer cell sensitivity to platinum derivatives and genomic stability
Authors: Jordheim Lars Petter , Cros‐Perrial Emeline , Matera Eva‐Laure , Bouledrak Karima , Dumontet Charles
Published: August 2014

Nucleotide excision repair (NER) is involved in the repair of DNA damage caused by platinum derivatives and has been shown to decrease the cytotoxic activity of these drugs. Because protein–protein interactions are essential for NER activity, we transfected human cancer cell lines (A549 and HCT116) with plasmids coding the amino acid sequences corresponding to the interacting domains between excision repair cross‐complementation group 1 (ERCC1) and xeroderma pigmentosum, complementation group A (XPA), as well as ERCC1 and xeroderma pigmentosum, complementation group F (XPF), all NER proteins. Using the 3‐(4,5‐dimethyl‐2 thiazoyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay and annexin V staining, we showed that transfected A549 cells were sensitized 1.2–2.2‐fold to carboplatin and that transfected HCT116 cells were sensitized 1.4–5.4‐fold to oxaliplatin in vitro. In addition, transfected cells exhibited modified in vivo sensitivity to the same drugs. Finally, in particular cell models of the interaction between ERCC1 and XPF, DNA repair was decreased, as evidenced by increased phosphorylation of the histone 2AX after exposure to mitomycin C, and genomic instability was increased, as determined by comparative genomic hybridization studies. The results indicate that the interacting peptides act as dominant negatives and decrease NER activity through inhibition of protein–protein interactions.
Systemic administration of 2‐hydroxypropyl‐β‐cyclodextrin to symptomatic Npc1‐deficient mice slows cholesterol sequestration in the major organs and improves liver function
Authors: Lopez Adam M , Terpack Sandi J , Posey Kenneth S , Liu Benny , Ramirez Charina M , Turley Stephen D
Published: August 2014

In Niemann–Pick type C (NPC) disease, loss‐of‐function mutations in either NPC1 or NPC2 result in progressive accumulation of unesterified cholesterol (UC) and glycosphingolipids in all organs, leading to neurodegeneration, pulmonary dysfunction and sometimes liver failure. There is no cure for this disorder. Studies using primarily NPC mouse models have shown that systemic administration of 2‐hydroxypropyl‐β‐cyclodextrin (2HPβCD), starting in early neonatal life, diminishes UC accumulation in most organs, slows disease progression and extends lifespan. The key question now is whether delaying the start of 2HPβCD treatment until early adulthood, when the amount of entrapped UC throughout the body is markedly elevated, has any of the benefits found when treatment begins at 7 days of age. In the present study, Npc1−/− and Npc1+/+ mice were given saline or 2HPβCD subcutaneously at 49, 56, 63 and 70 days of age, with measurements of organ weights, liver function tests and tissue cholesterol levels performed at 77 days. In Npc1−/− mice, treatment with 2HPβCD from 49 days reduced whole‐liver cholesterol content at 77 days from 33.0 ± 1.0 to 9.1 ± 0.5 mg/organ. Comparable improvements were seen in other organs, such as the spleen, and in the animal as a whole. There was a transient increase in biliary cholesterol concentration in Npc1−/− mice after 2HPβCD. Plasma alanine aminotransferase and aspartate aminotransferase activities in 77‐day‐old 2HPβCD‐treated Npc1−/− mice were reduced compared with saline‐treated controls. The lifespan of Npc1−/− mice given 2HPβCD marginally exceeded that of the saline‐treated controls (99 ± 1.1 vs 94 ± 1.4 days, respectively; P < 0.05). Thus, 2HPβCD is effective in mobilizing entrapped cholesterol in late‐stage NPC disease leading to improved liver function.
Vasorelaxation induced by methyl cinnamate, the major constituent of the essential oil of Ocimum micranthum, in rat isolated aorta
Authors: Vasconcelos‐Silva Alfredo Augusto , de Lima Francisco José Batista , de Brito Teresinha Silva , Lahlou Saad , Magalhães Pedro Jorge Caldas
Published: August 2014

The aim of the present study was to investigate the vascular effects of the E‐isomer of methyl cinnamate (E‐MC) in rat isolated aortic rings and the putative mechanisms underlying these effects. At 1–3000 μmol/L, E‐MC concentration‐dependently relaxed endothelium‐intact aortic preparations that had been precontracted with phenylephrine (PHE; 1 μmol/L), with an IC50 value (geometric mean) of 877.6 μmol/L (95% confidence interval (CI) 784.1–982.2 μmol/L). These vasorelaxant effects of E‐MC remained unchanged after removal of the vascular endothelium (IC50 725.5 μmol/L; 95% CI 546.4–963.6 μmol/L) and pretreatment with 100 μmol/L NG‐nitro‐l‐arginine methyl ester (IC50 749.0 μmol/L; 95% CI 557.8–1005.7 μmol/L) or 10 μmol/L 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (IC50 837.2 μmol/L; 95% CI 511.4–1370.5 μmol/L). Over the concentration range 1–3000 μmol/L, E‐MC relaxed K+‐induced contractions in mesenteric artery preparations (IC50 314.5 μmol/L; 95% CI 141.9–697.0 μmol/L) with greater potency than in aortic preparations (IC50 1144.7 μmol/L; 95% CI 823.2–1591.9 μmol/L). In the presence of a saturating contractile concentration of K+ (150 mmol/L) in Ca2+‐containing medium combined with 3 μmol/L PHE, 1000 μmol/L E‐MC only partially reversed the contractile response. In contrast, under similar conditions, E‐MC nearly fully relaxed PHE‐induced contractions in aortic rings in a Ba2+‐containing medium. In preparations that were maintained under Ca2+‐free conditions, 600 and 1000 μmol/L E‐MC significantly reduced the contractions induced by exogenous Ca2+ or Ba2+ in KCl‐precontracted preparations, but not in PHE‐precontracted preparations (in the presence of 1 μmol/L verapamil). In addition, E‐MC (1–3000 μmol/L) concentration‐dependently relaxed the contractions induced by 2 mmol/L sodium orthovanadate. Based on these observations, E‐MC‐induced endothelium‐independent vasorelaxant effects appear to be preferentially mediated by inhibition of plasmalemmal Ca2+ influx through voltage‐dependent Ca2+ channels. However, the involvement of a myogenic mechanism in the effects of E‐MC is also possible.
Effects of sildenafil on nanostructural and nanomechanical changes in mitochondria in an ischaemia‐reperfusion rat model
Authors: Lee Kyung Hye , Kwon Sung Jin , Woo Jong‐Shin , Lee Gi‐Ja , Lee So‐Ra , Jang Hyun‐Hee , Kim Hyun Soo , Kim Jung Wook , Park Hun Kuk , Cho Kyu Seok , Kim Weon
Published: August 2014

Sildenafil exerts cardioprotective effects by activating the opening of mitochondrial ATP‐sensitive potassium channels to attenuate ischaemia–reperfusion (IR) injury. In the present study, we used atomic force microscopy (AFM) to investigate changes in mitochondrial morphology and properties to assess sildenafil‐mediated cardioprotection in a rat myocardial infarction model. To investigate the cardioprotective effects of sildenafil, we used an in vivo Sprague‐Dawley rat model of IR. Rats were randomly divided into three groups: (i) sham‐operated rats (control; n = 5); (ii) IR‐injured rats treated with vehicle (normal saline; IR; n = 10); and (iii) IR‐injured rats treated with 0.75 mg/kg, i.p., sildenafil (IR + Sil; n = 10). Morphological and mechanical changes to mitochondria were analysed by AFM. Infarct areas were significantly reduced in sildenafil‐treated rats (7.8 ± 3.9% vs 20.4 ± 7.0% in the sildenafil‐treated and untreated IR groups, respectively; relative reduction 62%; P < 0.001). Analysis of mitochondria by AFM showed that IR injury significantly increased the areas of isolated mitochondria compared with control (24 150 ± 18 289 vs 1495 ± 1139 nm2, respectively; P < 0.001), indicative of mitochondrial swelling. Pretreatment with sildenafil before IR injury reduced the mitochondrial areas (7428 ± 3682 nm2; P < 0.001; relative reduction 69.2% compared with the IR group) and ameliorated the adhesion force of mitochondrial surfaces. Together, these results suggest that sildenafil has cardioprotective effects against IR injury in a rat model by improving the morphological and mechanical characteristics of mitochondria.
Role of peripheral purinoceptors in the development of bee venom‐induced nociception: A behavioural and electrophysiological study in rats
Authors: Li Li , Luo Rong , Fan Pei , Guo Yuan , Wang Hui‐sheng , Ma Shao‐jie , Zhao Yan
Published: August 2014

Colocalization of purinergic P2X and P2Y receptors in dorsal root ganglion sensory neurons implies that these receptors play an integrative role in the nociceptive transmission process under inflammatory conditions. In the present study, behavioural and in vivo electrophysiological methods were used to examine the peripheral role of P2 receptors in the persistent nociceptive responses induced by subcutaneous bee venom injection (2 mg/mL) in. Sprague‐Dawley rats Local pretreatment with the wide‐spectrum P2 receptor antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS; 1 mmol/L, 50 μL) 10 min prior to s.c. bee venom injection significantly suppressed the duration of spontaneous nociceptive lifting/licking behaviour, inhibited mechanical hyperalgesia and decreased the firing of spinal dorsal horn wide dynamic range neurons in response to bee venom, without affecting primary thermal and mirror‐image hyperalgesia. The localized antinociceptive action of PPADS was not due to a systemic effect, because application of the same dose of PPADS to the contralateral side was not effective. The results suggest that activation of peripheral P2 receptors is involved in the induction of nociceptive responses, mechanical hyperalgesia and the excitation of sensory spinal neurons.
CYP2C19*17 increases clopidogrel‐mediated platelet inhibition but does not alter the pharmacokinetics of the active metabolite of clopidogrel
Authors: Pedersen Rasmus Steen , Nielsen Flemming , Stage Tore Bjerregaard , Vinholt Pernille Just , el Achwah Alaa Bilal , Damkier Per , Brosen Kim
Published: August 2014

The aim of the present study was to determine the impact of CYP2C19*17 on the pharmacokinetics and pharmacodynamics of the active metabolite of clopidogrel and the pharmacokinetics of proguanil. Thus, we conducted an open‐label two‐phase cross‐over study in 31 healthy male volunteers (11 CYP2C19*1/*1, 11 CYP2C19*1/*17 and nine CYP2C19*17/*17). In Phase A, the pharmacokinetics of the derivatized active metabolite of clopidogrel (CAMD) and platelet function were determined after administration of a single oral dose of 600 mg clopidogrel (Plavix; Sanofi‐Avensis, Horsholm, Denmark). In Phase B, the pharmacokinetics of proguanil and its metabolites cycloguanil and 4‐chlorphenylbiguanide (4‐CPB) were determined in 29 of 31 subjects after a single oral dose of 200 mg proguanil given as the combination drug Malarone (GlaxoSmithKline Pharma, Brondby, Denmark). Significant correlations were found between the area under the time–concentration curve (AUC0–∞) of CAMD and both the absolute ADP‐induced P2Y12 receptor‐activated platelet aggregation (r = −0.60, P = 0.0007) and the percentage inhibition of aggregation (r = 0.59, P = 0.0009). In addition, the CYP2C19*17/*17 and CYP2C19*1/*17 genotype groups had significantly higher percentage inhibition of platelet aggregation compared with the CYP2C19*1/*1 subjects (geometric mean percentage inhibition of 84%, 73% and 63%, respectively; P = 0.014). Neither the absolute ADP‐induced P2Y12 receptor‐activated platelet aggregation, exposure to CAMD nor the pharmacokinetic parameters of proguanil, cycloguanil and 4‐CPB exhibited any significant differences among the genotype groups. In conclusion, carriers of CYP2C19*17 exhibit higher percentage inhibition of platelet aggregation, but do not have significantly lower absolute P2Y12 receptor‐activated platelet aggregation or higher exposure to the active metabolite after a single oral administration of 600 mg clopidogrel.