bluuebunny/crossref_metadata_2025 huggingface dataset:
Translating Key Competences into the School Curriculum: lessons from the Polish experience
Authors: Dąbrowski Mirosław , Wiśniewski Jerzy
Published: August 2011

Over the last 20 years, Poland has gone through a major transition process in which the challenges for education in terms of new approaches to learning and teaching have been compounded by broader changes such as the democratisation of structures and processes and the major economic and social changes. This article is a case study that examines the early stages of significant shifts in the learning and teaching process, the stepped approach that was taken and the different international influences. It was decided to focus on the top‐down, policy level actions in order to trace how influences have shaped current policy on outcomes‐based approaches and key competences, which are increasingly implemented in schools today.

The Polish education and training system has been through a complex series of reforms, many simultaneously. The introduction of outcome‐based approaches and key competences is part of much broader reforms that have affected mindsets and attitudes by having addressed the structure of the system (e.g. the length of compulsory education), school governance, the roles of principals and teachers, teacher training, etc. Parents' expectations have evolved and students are growing up in a much more connected environment with Internet and social networks and an exponential development of access to ICT and the need for digital competences and a range of key competences for lifelong learning and work (Gordon et al., 2009). Although change has taken place at all levels and in all sub‐sectors of the system, this article focuses on general education in primary and secondary schools.
Measuring Young People's Citizenship Competences
Authors: ten Dam Geert , Geijsel Femke , Reumerman Rene , Ledoux Guuske
Published: August 2011

Citizenship has recently been introduced into the educational curriculum. Instruments to determine the effects of citizenship education are scarce. In this article, the concept of citizenship competences is explored in order to develop a measurement instrument. Four social tasks were derived from the literature as representative of young people's citizenship practices: acting democratically, acting in a socially responsible manner, dealing with conflicts, and dealing with differences. What adequate fulfilment of each social task presupposes in terms of knowledge, attitudes, skills, and reflection is defined per task and operationalised into items for a questionnaire. The sample (N = 16,000) concerns a representative sample of students in grade 6 and grade 9. Confirmatory factor analyses were conducted to determine the extent to which the structure in the data corresponded to the structure expected on theoretical grounds. The study reveals a reliable and valid instrument for the measurement of young people's citizenship competences. Future research should provide insight into how these competences relate to citizenship behaviour and whether measures of citizenship competences and behaviour will help schools to evaluate the effectiveness of their efforts.
Computers and School: Indian and French students' discourse
Authors: Cerisier Jean‐François , Popuri Aruna
Published: August 2011

The use of digital technologies by young people and the impact of e‐learning have been the subject of a significant number of studies carried out worldwide. However, when it comes to student perceptions about the place and role of these technologies in their lives, research looks towards university students. This article aims to understand what the technologies represent for school students in their personal and school lives. It is based on a study that brings together two contexts, representing opposing cultures and trends: France where the policy on school computers has been in place for more than two decades and India where the government has only recently begun to make efforts to overcome the digital divide. This study conducted in the two countries in 2009 among 960 young people aged between 11 and 18 shows the importance of schools in constructing private spaces to be shared with peers, a role that has long been attributed to home computers. This article thus provides elements of explanation for the relative disenchantment that young people feel for the school‐related uses of the technologies. For them, school is not about individualist autonomous learning, but about learning from teachers as a group.
Recognition is Deserved, Qualifications are Merited. Where Does that Leave Fairness in Accreditation?
Authors: Gibbs Paul , Armsby Pauline
Published: August 2011

This article contextualises the use of accreditation for prior experiential learning (APEL) in European higher education by analysing the notions of desert and merit. We propose that the credentialising of certain types of knowledge can lead to a narrow definition of education which merely endeavours to serve consumer imperatives so as to market the individual in the work place rather than develop the essence of their being. The article advocates judgement not rules, codes or descriptors in making assessments of the worth of the personal and professional knowledge , experience and practices of claimants. We then argue that without such mechanistic criteria desert rather than merit should hold sway in the making of assessments. Moreover, we propose that desert more fairly represents an individual's achievements for the purposes of the owner of the achievement and for those would wish to make decsions based upon them.
The Winds of Change in Russian Higher Education: is the East moving West?
Authors: Timoshenko Konstantin
Published: August 2011

In the last 30 years, major changes have taken place in the public sector worldwide under the rubric of New Public Management [NPM]. The education sector is perhaps one of the key areas drawing an intense interest and discussion in the wake of NPM. The Russian State seems to be no longer an exception to this global trend. In line with this, the Russian education sector was declared as a large‐scale top priority national project in the late summer of 2005, which was aimed to help raise the living standards of each Russian citizen. This empirical paper seeks to reveal the major institutional and legal changes taking place in Russian higher education over time. This insight is vital as it points to the contexts in which Russian public universities operate. To make the acquaintance of a system of Russian higher education, this research sketches its evolution. It commences from the Soviet era to the present time, highlighting the most significant government initiatives.
Satisfaction with Higher Education: critical data for student development
Authors: de Lourdes Machado Maria , Brites Rui , Magalhães António , Sá Maria José
Published: August 2011

Higher education is a mainstay in the development and support of the economic, social and cultural development of the global society. Throughout history, academic institutions have sought to respond to the demands of endlessly changing and evolving environmental conditions. However, in the 21st century, a number of significant factors are changing the higher education landscape and challenging higher education institutions (HEIs) to interpret the vital needs of contemporary society to stimulate and enhance student development. Student development is an all‐embracing concept that involves research focusing on students from recruitment to placement. Assuming that meeting student needs and stimulating and enhancing their development are crucial challenges for higher education institutions worldwide, the article focuses on a national study in Portugal designed to measure students’ expectations and satisfaction with their experience. On the basis of a nationwide survey, it examines these in the various types of higher education institutions in Portugal.
ALTRUISM AND THE ADMINISTRATION OF THE UNIVERSE: KIRTLEY FLETCHER MATHER ON SCIENCE AND VALUES
Authors: Davis Edward B.
Published: August 2011

Abstract.  Few American scientists have devoted as much attention to religion and science as Harvard geologist Kirtley Fletcher Mather (1888–1978). Responding to antievolutionism during the 1920s, he taught Sunday School classes, assisted in defending John Scopes, and wrote Science in Search of God (1928). Over the next 40 years, Mather explored the place of humanity in the universe and the presence of values in light of what he often called “the administration of the universe,” a term and concept he borrowed from his former teacher, geologist Thomas Chrowder Chamberlin. Human values, including cooperation and altruism, had emerged in such a context: “the administrative directive toward orderly organization of increasingly complex systems transcends the urge for survival.” He was also active in the early years of the Institute on Religion in an Age of Science, an organization created by his good friends Ralph Wendell Burhoe and Harlow Shapley.
THE UNIFORMITY OF NATURAL LAWS IN VICTORIAN BRITAIN: NATURALISM, THEISM, AND SCIENTIFIC PRACTICE
Authors: Stanley Matthew
Published: August 2011

Abstract.  A historical perspective allows for a different view on the compatibility of theistic views with a crucial foundation of modern scientific practice: the uniformity of nature, which states that the laws of nature are unbroken through time and space. Uniformity is generally understood to be part of a worldview called “scientific naturalism,” in which there is no room for divine forces or a spiritual realm. This association comes from the Victorian era, but a historical examination of scientists from that period shows that uniformity was an important part of both theistic and naturalistic worldviews. Victorian efforts to maintain the viability of miracles and divine action within a universe ruled by natural laws receives special attention. The methodological practices of theistic and naturalistic scientists in the nineteenth century were effectively indistinguishable despite each group's argument that uniformity was closely dependent on their worldview. This similarity is used to reexamine both the reasons for the decline of the role of religion within the scientific community and claims made by the intelligent design movement about the relationship of science and religion.
WHAT IS “MYTHIC REALITY”?
Authors: Segal Robert A.
Published: August 2011

Abstract.  The topic of the March 2011 symposium in Zygon is “The Mythic Reality of the Autonomous Individual.” Yet few of the contributors even discuss “mythic reality.” Of the ones who do, most cavalierly use “myth” dismissively, as simply a false belief. Rather than reconciling myth with reality, they oppose myth to reality. Their view of myth is by no means unfamiliar or unwarranted, but they need to recognize other views of myth and to defend their own. Above all, they need to appreciate the grip that any belief aptly labelled myth has—a grip that holds at least as much for a false belief as for a true one.
HINDUISM AND SCIENCE: THE STATE OF THE SOUTH ASIAN SCIENCE AND RELIGION DISCOURSE
Authors: Dorman Eric R.
Published: August 2011

Abstract.  The science and religion discourse in the Western academy, though expansive, has not paid significant enough attention to South Asian views, particularly those from Hindu thought. This essay seeks to address this issue in three parts. First, I present the South Asian standpoint as it currently relates to the science and religion discourse. Second, I survey and evaluate some available literature on South Asian approaches to the science and religion discourse. Finally, I promote three possible steps forward: (1) the literature must shift from high Hindu philosophical religion to the more prevalent bhakti traditions, (2) the Indian context must be understood in its own right without metaphysical assumptions attached to the concepts of science and religion, and (3) most importantly, concepts unique to the Indian worldview, such as dharma, maya, and cit, must receive better treatment in translation in order to facilitate a more accurate exchange of ideas across cultural boundaries.
MAKING ROOM FOR FAITH IN AN AGE OF SCIENCE: A RESPONSE TO DAVID WISDO
Authors: Ruse Michael
Published: August 2011

Abstract.  I respond to the criticisms of David Wisdo of my position on the relationship between science and religion. I argue that although he gives a full and fair account of my position, he fails to grasp fully my use of the metaphorical basis of modern science in my argument that, because of its mechanistic commitment, there are some questions that science not only does not answer but that science does not even attempt to answer. Hence, my position stands and plays a crucial role in our understanding of the science–religion relationship.
REVIVING CHRISTIAN HUMANISM: SCIENCE AND RELIGION*
Authors: Browning Don S.
Published: August 2011

Abstract.  A possible consequence of the dialogue between science and religion is a revived religious humanism—a firmer grasp of the historical and phenomenological meanings of the great world religions correlated with the more accurate explanations of the rhythms of nature that natural science can provide. The first great expressions of religious humanism in the West emerged when Jewish, Christian, and Islamic scholars sat in the same libraries in Spain and Sicily, studying and translating the lost manuscripts of Aristotle in the ninth and tenth centuries to understand his ethics, epistemology, and psychobiology. In our day, the science‐religion dialogue—exemplified by interaction among psychology, spirituality, and psychotherapy—will best support such a revival if guided by the philosophical resources of critical hermeneutics (sometimes called hermeneutical realism) supplemented by William James's brand of phenomenology and pragmatism. Here, I develop primarily the contributions of Paul Ricoeur to hermeneutic realism and his unique ability to find a place for the natural sciences within hermeneutic phenomenology in his formula of understanding‐explanation‐understanding.
PSYCHOLOGY, RELIGION, AND CRITICAL HERMENEUTICS: DON BROWNING AS “HORIZON ANALYST”
Authors: Cooper Terry D.
Published: August 2011

Abstract.  Don Browning's career involved a deep exploration into the frequently hidden philosophical assumptions buried in various forms of psychotherapeutic healing. These healing methodologies were based on metaphors and metaphysical assumptions about both the meaning of human fulfillment and the ultimate context of our lives. All too easily, psychological theories put forward philosophical anthropologies while claiming to be operating within a modest, empirical approach. Browning does not fault or criticize these psychotherapeutic enterprises for making such claims because he thinks these claims are implicit in all discussions of psychological health. But he does fault these methodologies for not being more forthcoming about their shift from a narrow empirical investigation to a broad‐ranging philosophical and even quasireligious orientation. Browning can be described as a “horizon analyst” who constantly pulled back the curtains and helped us see the deeper symbols, images, and metaphysical assumptions behind our psychological investigations.
THE ARTFUL HUMANISM OF DON BROWNING
Authors: Wildman Wesley J.
Published: August 2011

Abstract.  Don Browning's intellectual artfulness is particularly evident in three areas: as analyst of basic assumptions in intellectual systems, as fundamental ethicist, and as mediating theologian. His work in each area has been extraordinarily fruitful, both theoretically and practically. In each area, however, his skillful handling of complex issues also has subtle limitations. This paper identifies those limitations, analyzes them as facets of an articulate but preemptive defense of a preferred theological outlook, and thus as a limited failure of Browning's otherwise broadly successful implementation of a critical hermeneutical method.
CHRISTIANITY'S MIXED CONTRIBUTIONS TO CHILDREN'S RIGHTS
Authors: Browning Don S. , Witte, Jr John
Published: August 2011

Abstract. In this paper, which was among Don Browning's last writings before he died, we review and evaluate the main arguments against the United Nations Convention on the Rights of the Child (the “CRC”) that conservative American Christians in particular have opposed. While we take their objections seriously, we think that, on balance, the CRC is worthy of ratification, especially if it is read in light of the profamily ethic that informs the CRC and many earlier human rights instruments. More fundamentally, we think that the CRC captures some of the very best traditional Western legal and theological teachings on marriage, family, and children, which we retrieve and reconstruct for our day.
A NATURAL LAW THEORY OF MARRIAGE*
Authors: Browning Don S.
Published: August 2011

Abstract.  For the past two decades, I have been developing an integrative Christian marriage theory, based in part on a grounding concept of natural law and an overarching theory of covenant. The natural law part of this theory starts with an account of the natural facts, conditions, interests, needs, and qualities of human life, interaction, and generation—what I call the “premoral” goods or realities of life. It then identifies the natural inclinations of humans to form enduring and exclusive monogamous marriages and to preserve these units as the central site for intimacy, procreation, and nurture of children. In this paper, I first summarize this natural law theory of marriage and then compare it to the formulations of other modern Christian thinkers. I also defend this theory against various modern critics of natural law—in part by reinterpreting some traditional natural law teachings that in my view have been misunderstood, in part by looking at the interesting convergences between the insights into sex, marriage, and family life offered by contemporary Christian theological ethicists and by evolutionary biologists and biological anthropologists.
Self‐assessed consequences of unemployment on individual wellbeing and family relationships: A study of unemployed women and men in Finland
Authors: Weckström Sirpa
Published: August 2011

Weckström S. Self‐assessed consequences of unemployment on individual wellbeing and family relationships: a study of unemployed women and men in Finland

The present study investigated how family situation and gender affect the experience of unemployment. The sample consisted of 494 Finnish women and 387 Finnish men who had been registered as unemployed for at least 3 months. The main method used in the study was analysis of covariance. Women assessed the consequences of unemployment on their individual wellbeing and on the parent–child relationship less negatively than men, but there was no corresponding gender difference concerning spousal relationship. Lone mothers experienced the change in individual wellbeing slightly more negatively than women in other family situations; this difference was in part related to financial strain. Financial strain and non‐financial work motivation predicted negative changes in individual wellbeing and in spousal relationship for both genders. Parent–child relationships were, however, independent from these variables. The way family relationships were affected was connected to changes in individual wellbeing.
Securing the Majority: Living through Uncertainty in Jakarta
Authors: SIMONE ABDOUMALIQ , RAO VYJAYANTHI
Published: August 2011

Drawing on research in Jakarta, this article reconsiders the importance of heterogeneous economic practices in the remaking of central‐city districts in ways that provide ongoing platforms of residence and operation for residents from wide‐ranging walks of life. The emphasis on good governance and rights‐based discourses have sometimes occluded the operations of urban real economies that, even if waning in the face of the proliferation of mega‐developments, constitute the critical capacity of the majority of urban residents' efforts to secure a viable place in the city.

À partir de recherches menées à Jakarta, cet article réexamine l'importance des pratiques économiques hétérogènes en matière de remaniement des quartiers centraux selon des modalités qui offrent des bases de résidence et d'activité permanentes à des résidents venus d'horizons très divers. L'accent mis sur les discours prônant une gouvernance efficiente et le respect des droits a parfois bloqué les opérations des économies réelles urbaines qui, bien qu'en déclin face à la prolifération des méga‐aménagements, constituent la capacité cruciale dans le cadre des efforts de la majorité des résidents urbains pour se procurer un lieu viable dans la ville.
Extracellular matrix molecules implicated in hypertrophic and keloid scarring
Authors: Sidgwick G.P. , Bayat A.
Published: August 2011

Tissue regeneration repairs the fabric of the skin to maintain homeostasis after injury. The expression and proliferation of extracellular matrix (ECM) molecules in the dermis, mediated by a range of growth factors and cytokines, is a fundamental element of wound repair. Previous work focused on how these complex molecular mechanisms relate to the formation of raised dermal scars, including keloid and hypertrophic scars, characterized by excessive deposition of ECM molecules. However, the mechanisms in the wound repair pathway which lead to the differential expression and organization of ECM molecules observed in different types of scar tissue are not fully understood. To summarize what is known about the expression and composition of ECM molecules in abnormal scarring, an extensive search of the literature was conducted, focusing on keywords connected to skin scarring, hypertrophic scars and keloid disease. The transcription and translation of collagen I and III, fibronectin, laminin, periostin and tenascin are all increased in raised dermal scar tissue. However, hyaluronic acid, dermatopontin and decorin are decreased, and the expression and localisation of fibrillin and elastin fibres in the dermis are altered compared with normal skin and scars. Recent whole genome profiling and proteomic studies have led to the identification of regulatory elements with different expression profiles in hypertrophic and keloid tissue. If the mechanisms of raised dermal scar formation are to be elucidated and effective therapeutic treatments developed, an integrated approach to research is required, focussing on the interactions between ECM molecules, regulatory elements and pathways.
Osteopontin expression in plasma of melanoma patients and in melanocytic tumours
Authors: Maier T. , Laubender R.P. , Sturm R.A. , Klingenstein A. , Korting H.C. , Ruzicka T. , Berking C.
Published: August 2011

Background  While the serological tumour marker S100 is well established for the detection of metastatic melanoma, the extracellular matrix protein osteopontin (OPN) seems to be a promising novel marker for invasive melanoma.

Objectives  We analysed the potential of OPN as a serological tumour marker for metastatic melanoma and evaluated its combination with S100 and lactate dehydrogenase (LDH) levels to increase the reliability of these biomarkers for the detection of metastatic disease.

Methods  We examined OPN in the peripheral blood of 110 melanoma patients using enzyme‐linked immunosorbent assay and combined it with S100 and LDH levels. In addition, the protein expression of OPN was analysed in tissue sections of melanocytic nevi and melanomas of different progression stages by immunohistochemistry.

Results  The independent comparison of S100 and OPN levels in metastatic vs. non‐metastatic patients revealed a P‐value <0.001 respectively. The predictiveness of OPN, S100 and LDH was 0.85, 0.89 and 0.69 as measured by the area under the receiver operating curve (AUC) respectively, while the combination of the two biomarkers OPN and S100 showed an AUC of 0.97. The optimal cut‐off of the combination of OPN and S100 yielded a specificity of 85.9% and a sensitivity of 95.5%.

By immunohistochemistry, OPN protein expression was detected in 29% (7/24) of melanocytic nevi, 67% (30/45) of primary melanomas and 39% (7/18) of metastatic melanomas.

Conclusions  Together, OPN seems to be a promising novel biomarker for the detection of metastatic disease in melanoma patients, showing elevated plasma levels in metastatic disease and increased protein expression in melanocytic lesions. The combination of OPN with the well‐established tumour marker S100 might increase the prediction of metastases.
The fatty acid oxidation product 15‐A3t‐Isoprostane is a potent inhibitor of NFκB transcription and macrophage transformation
Authors: Brooks Joshua D. , Musiek Erik S. , Koestner Tyler R. , Stankowski Jeannette N. , Howard Jocelyn R. , Brunoldi Enrico M. , Porta Alessio , Zanoni Giuseppe , Vidari Giovanni , Morrow Jason D. , Milne Ginger L. , McLaughlin BethAnn
Published: August 2011

J. Neurochem. (2011) 119, 604–616.

Fatty acids such as eicosapentaenoic acid (EPA) have been shown to be beneficial for neurological function and human health. It is widely thought that oxidation products of EPA are responsible for biological activity, although the specific EPA peroxidation product(s) which exert these responses have not yet been identified. In this work we provide the first evidence that the synthesized representative cyclopentenone IsoP, 15‐A3t‐IsoP, serves as a potent inhibitor of lipopolysaccharide‐stimulated macrophage activation. The anti‐inflammatory activities of 15‐A3t‐IsoP were observed in response not only to lipopolysaccharide, but also to tumor necrosis factor alpha and IL‐1b stimulation. Subsequently, this response blocked the ability of these compounds to stimulate nuclear factor kappa b (NFκB) activation and production of proinflammatory cytokines. The bioactivity of 15‐A3t‐IsoP was shown to be dependent upon an unsaturated carbonyl residue which transiently adducts to free thiols. Site directed mutagenesis of the redox sensitive C179 site of the Ikappa kinase beta subunit, blocked the biological activity of 15‐A3t‐IsoP and NFκB activation. The vasoprotective potential of 15‐A3t‐IsoP was underscored by the ability of this compound to block oxidized lipid accumulation, a critical step in foam cell transformation and atherosclerotic plaque formation. Taken together, these are the first data identifying the biological activity of a specific product of EPA peroxidation, which is formed in abundance in vivo. The clear mechanism linking 15‐A3t‐IsoP to redox control of NFκB transcription, and the compound’s ability to block foam cell transformation suggest that 15‐A3t‐IsoP provides a unique and potent tool to provide vaso‐ and cytoprotection under conditions of oxidative stress.
Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of Coffin‐Lowry syndrome
Authors: Schneider Anne , Mehmood Tahir , Pannetier Solange , Hanauer André
Published: August 2011

J. Neurochem. (2011) 119, 447–459.

Coffin–Lowry syndrome is a syndromic form of mental retardation caused by mutations of the Rps6ka3 gene encoding ribosomal s6 kinase (RSK)2. RSK2 belongs to a family containing four members in mammals: RSK1–4. RSKs are serine/threonine kinases and cytosolic substrates of extracellular signal‐regulated kinase (ERK) in the Ras/MAPK signaling pathway. RSK2 is highly expressed in the hippocampus, and mrsk2_KO mice display spatial learning and memory impairment. In the present study, we provide evidence of abnormally increased phosphorylation of ERK1/2 in the hippocampus of mrsk2_KO mice. Further studies based on cultured hippocampal neurons revealed that glutamate activates ERK1/2 and RSKs, and confirmed a stronger activation of ERK1/2 in mrsk2_KO neurons than in WT cells. We, thus, provide further evidence that RSK2 exerts a feedback inhibitory effect on the ERK1/2 pathway. We also observed a transient sequestration of P‐ERK1/2 in the cytoplasm upon glutamate stimulation. In addition, the transcription factors cAMP response element binding and Ets LiKe gene1 show over‐activation in RSK2‐deficient neurons. Finally, c‐Fos, Zif268 and Arc were significantly over‐expressed in mrsk2_KO neurons upon glutamate stimulation. Importantly, the increased phosphorylation of other RSK family members observed in mutant neurons was unable to compensate for RSK2 deficiency. This aberrant ERK1/2 signaling can influence various neuronal functions, and thus play a significant role in cognitive dysfunction in mrsk2_KO mice and in the Coffin‐Lowry syndrome.
The effects of chronic treatment with mood stabilizers on the rat hippocampal post‐synaptic density proteome
Authors: Nanavati Dhaval , Austin Daniel R. , Catapano Lisa A. , Luckenbaugh David A. , Dosemeci Ayse , Manji Husseini K. , Chen Guang , Markey Sanford P.
Published: August 2011

J. Neurochem. (2011) 119, 617–629.

Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. There is growing evidence that the disease is correlated with disruptions in synaptic plasticity cascades involved in cognition and mood regulation. Alleviating the symptoms of bipolar disorder involves chronic treatment with mood stabilizers like lithium or valproate. These two structurally dissimilar drugs are known to alter prominent signaling cascades in the hippocampus, but their effects on the post‐synaptic density complex remain undefined. In this work, we utilized mass spectrometry for quantitative profiling of the rat hippocampal post‐synaptic proteome to investigate the effects of chronic mood stabilizer treatment. Our data show that in response to chronic treatment of mood stabilizers there were not gross qualitative changes but rather subtle quantitative perturbations in post‐synaptic density proteome linked to several key signaling pathways. Our data specifically support the changes in actin dynamics on valproate treatment. Using label‐free quantification methods, we report that lithium and valproate significantly altered the abundance of 21 and 43 proteins, respectively. Seven proteins were affected similarly by both lithium and valproate: Ank3, glutamate receptor 3, dynein heavy chain 1, and four isoforms of the 14‐3‐3 family. Immunoblotting the same samples confirmed the changes in Ank3 and glutamate receptor 3 abundance. Our findings support the hypotheses that BPD is a synaptic disorder and that mood stabilizers modulate the protein signaling complex in the hippocampal post‐synaptic density.
Ovariectomy in grasshoppers increases somatic storage, but proportional allocation of ingested nutrients to somatic tissues is unchanged
Authors: Judd Evan T. , Wessels Frank J. , Drewry Michelle D. , Grove Matthew , Wright Katharine , Hahn Daniel A. , Hatle John D.
Published: August 2011

Reduced reproduction increases storage and extends lifespan in several animal species. The disposable soma hypothesis suggests this life extension occurs by shifting allocation of ingested nutrients from reproduction to the soma. A great deal of circumstantial evidence supports this hypothesis, but no direct tracking of nutrients has been performed in animals that are long‐lived because of direct reduction in reproduction. Here, we use the stable isotopes to track carbon and nitrogen from ingestion to somatic organs in long‐lived, ovariectomized grasshoppers. Three estimates of somatic storage (viz., quantity of hemolymph storage proteins, amount of femur muscle carbohydrates, and size of the fat body) all doubled upon ovariectomy. In stark contrast, ovariectomy did not increase the proportion of these tissues that were made from recently ingested foods. In other words, the physiology underlying relative allocation to these somatic tissues was not affected by ovariectomy. Thus, at the level of whole tissue storage, these results are consistent with a trade‐off between reproduction and longevity. In contrast, our stable isotope data are inconsistent with the prediction that enhanced storage in ovariectomized females results from a physiological shift in allocation of ingested nutrients.
The H3K27 demethylase UTX‐1 regulates C. elegans lifespan in a germline‐independent, insulin‐dependent manner
Authors: Maures Travis J. , Greer Eric L. , Hauswirth Anna G. , Brunet Anne
Published: August 2011

Aging is accompanied by alterations in epigenetic marks that control chromatin states, including histone acetylation and methylation. Enzymes that reversibly affect histone marks associated with active chromatin have recently been found to regulate aging in Caenorhabditis elegans. However, relatively little is known about the importance for aging of histone marks associated with repressed chromatin. Here, we use a targeted RNAi screen in C. elegans to identify four histone demethylases that significantly regulate worm lifespan, UTX‐1, RBR‐2, LSD‐1, and T26A5.5. Interestingly, UTX‐1 belongs to a conserved family of histone demethylases specific for lysine 27 of histone H3 (H3K27me3), a mark associated with repressed chromatin. Both utx‐1 knockdown and heterozygous mutation of utx‐1 extend lifespan and increase the global levels of the H3K27me3 mark in worms. The H3K27me3 mark significantly drops in somatic cells during the normal aging process. UTX‐1 regulates lifespan independently of the presence of the germline, but in a manner that depends on the insulin‐FoxO signaling pathway. These findings identify the H3K27me3 histone demethylase UTX‐1 as a novel regulator of worm lifespan in somatic cells.
Expression, assembly and function of novel C‐terminal truncated variants of the mouse P2X7 receptor: re‐evaluation of P2X7 knockouts
Authors: Masin Marianela , Young Christopher , Lim KoiNi , Barnes Sara J , Xu Xing Jian , Marschall Viola , Brutkowski Wojciech , Mooney Elizabeth R , Gorecki Dariusz C , Murrell‐Lagnado Ruth
Published: August 2011

BACKGROUND AND PURPOSE Splice variants of P2X7 receptor transcripts contribute to the diversity of receptor‐mediated responses. Here, we investigated expression and function of C‐terminal truncated (ΔC) variants of the mP2X7 receptor, which are predicted to escape inactivation in one strain of P2X7−/− mice (Pfizer KO).

EXPERIMENTAL APPROACH Expression in wild‐type (WT) and Pfizer KO tissue was investigated by reverse transcription (RT)‐PCR and Western blot analysis. ΔC variants were also cloned and expressed in HEK293 cells to investigate their assembly, trafficking and function.

KEY RESULTS RT‐PCR indicates expression of a ΔC splice variant in brain, salivary gland (SG) and spleen from WT and Pfizer KO mice. An additional ΔC hybrid transcript, containing sequences of P2X7 upstream of exon 12, part of exon 13 followed in‐frame by the sequence of the vector used to disrupt the P2X7 gene, was also identified in the KO mice. By blue native (BN) PAGE analysis and the use of cross linking reagents followed by SDS‐PAGE, P2X7 trimers, dimers and monomers were detected in the spleen and SG of Pfizer KO mice. The molecular mass was reduced compared with P2X7 in WT mice tissue, consistent with a ΔC variant. When expressed in HEK293 cells the ΔC variants were inefficiently trafficked to the cell surface and agonist‐evoked whole cell currents were small. Co‐expressed with P2X7A, the ΔC splice variant acted in a dominant negative fashion to inhibit function.

CONCLUSIONS AND IMPLICATIONS Pfizer KO mice are not null for P2X7 receptor expression but express ΔC variants with reduced function.
Chronic blockade of cannabinoid CB2 receptors induces anxiolytic‐like actions associated with alterations in GABAA receptors
Authors: García‐Gutiérrez María S , García‐Bueno Borja , Zoppi Silvia , Leza Juan C , Manzanares Jorge
Published: August 2011

BACKGROUND AND PURPOSE The aim of this study was to explore the effects of CB2 receptor agonist and antagonist in the regulation of anxiety‐like behaviours.

EXPERIMENTAL APPROACHES Effects of acute and chronic treatment with the CB2 receptor agonist JWH133 and CB2 receptor antagonist AM630 were evaluated in the light‐dark box (LDB) and elevated plus maze (EPM) tests in Swiss ICR mice. CB2 receptor, GABAAα2 and GABAAγ2 gene and protein expression in the cortex and amygdala of mice chronically treated with JWH133 or AM630 were examined by RT‐PCR and Western blot. Effects of chronic AM630 treatment were evaluated in spontaneously anxious DBA/2 mice in LDB.

KEY RESULTS Acute JWH133 treatment failed to produce any effect. Acute AM630 treatment increased anxiety and was blocked by pre‐treatment with JWH133. Chronic JWH133 treatment increased anxiety‐like behaviour whereas chronic AM630 treatment was anxiolytic in LDB and EPM tests. Chronic AM630 treatment increased gene and reduced protein expression of CB2 receptors, GABAAα2 and GABAAγ2 in cortex and amygdala. Chronic JWH133 treatment resulted in opposite gene and protein alterations. In addition, chronic AM630 administration decreased the anxiety of DBA/2 mice in the LDB test.

CONCLUSIONS AND IMPLICATIONS The opposing behavioural and molecular changes observed after chronic treatment with AM630 or JWH133 support the key role of CB2 receptors in the regulation of anxiety. Indeed, the efficacy of AM630 in reducing the anxiety of the spontaneously anxious DBA/2 strain of mice strengthens the potential of the CB2 receptor as a new target in the treatment of anxiety‐related disorders.
Long‐term treatment with ivabradine in post‐myocardial infarcted rats counteracts f‐channel overexpression
Authors: Suffredini S , Stillitano F , Comini L , Bouly M , Brogioni S , Ceconi C , Ferrari R , Mugelli A , Cerbai E
Published: August 2011

BACKGROUND AND PURPOSE Recent clinical data suggest beneficial effects of ivabradine, a specific heart rate (HR)‐lowering drug, in heart failure patients. However, the mechanisms responsible for these effects have not been completely clarified. Thus, we investigated functional/molecular changes in If, the specific target of ivabradine, in the failing atrial and ventricular myocytes where this current is up‐regulated as a consequence of maladaptive remodelling.

EXPERIMENTAL APPROACH We investigated the effects of ivabradine (IVA; 10 mg·kg−1·day−1 for 90 days) on electrophysiological remodelling in left atrial (LA), left ventricular (LV) and right ventricular (RV) myocytes from post‐mycardial infarcted (MI) rats, with sham‐operated (sham or sham + IVA) rats as controls. If current was measured by patch‐clamp; hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channel isoforms and microRNA (miRNA‐1 and miR‐133) expression were evaluated by reverse transcription quantitative PCR.

KEY RESULTS Maximal specific conductance of If was increased in MI, versus sham, in LV (P < 0.01) and LA myocytes (P < 0.05). Ivabradine reduced HR in both MI and sham rats (P < 0.05). In MI + IVA, If overexpression was attenuated and HCN4 transcription reduced by 66% and 54% in LV and RV tissue, respectively, versus MI rats (all P < 0.05). miR‐1 and miR‐133, which modulate post‐transcriptional expression of HCN2 and HCN4 genes, were significantly increased in myocytes from MI + IVA.

CONCLUSION AND IMPLICATION The beneficial effects of ivabradine may be due to the reversal of electrophysiological cardiac remodelling in post‐MI rats by reduction of functional overexpression of HCN channels. This is attributable to transcriptional and post‐transcriptional mechanisms.
Long‐term adefovir plus lamivudine therapy does not decrease creatinine clearance in HBeAg‐negative chronic hepatitis B patients
Authors: Manolakopoulos Spilios , Striki Athanasia , Deutsch Melanie , Mela Maria , Ketikoglou Ioannis , Tzourmakliotis Dimitrios , Manesis Emanuel K. , Papatheodoridis George V.
Published: August 2011

Background/Aims

As there are concerns about potential nephrotoxicity of nucleotide analogues, we evaluated renal function parameters during long‐term adefovir and lamivudine combination therapy.

Methods

Forty‐six HBeAg‐negative patients with lamivudine‐resistance treated with adefovir and lamivudine for up to 90 months were included. Renal function was assessed by estimated creatinine clearance (eCCR) and compared with a matched control group of untreated inactive hepatitis B virus carriers.

Results

Serum HBV DNA became undetectable in 39 (85%) patients after a mean of 37 ± 21 months. Three (6.5%) patients developed virological breakthrough. Adefovir resistance was detected in two patients. At the end of follow up, there was a significant decrease in mean eCCR (95 ± 31–83 ± 30 ml/min, P = 0.003) in the treated patients with 16% presenting aeCCR decrease >30%. Similar changes in eCCR were observed in the control group (108 ± 28–96 ± 26 ml/min, P = 0.003). In multiple regression analysis, age and baseline eCCR were independent predictors of eCCR reduction.

Conclusions

Adefovir and lamivudine combination therapy is not an independent factor for significant renal dysfunction in HBeAg‐negative patients with lamivudine‐resistance. Baseline age and creatinine clearance are the only independent predictors of worsening renal function.
Multiple effects of honokiol on the life cycle of hepatitis C virus
Authors: Lan Keng‐Hsin , Wang Ying‐Wen , Lee Wei‐Ping , Lan Keng‐Li , Tseng Szu‐Han , Hung Li‐Rong , Yen Sang‐Hue , Lin Han‐Chieh , Lee Shou‐Dong
Published: August 2011

Background

Honokiol, a small active molecular compound extracted from magnolia, has recently been shown to inhibit hepatitis C virus (HCV) infection in vitro.

Aims

This study further characterized aspects of the HCV lifecycle affected by the antiviral functions of honokiol.

Methods

The influence of honokiol on HCV infection, entry, translation and replication was assessed in Huh‐7.5.1 cells using cell culture‐derived HCV (HCVcc), HCV pseudo‐type (HCVpp) and sub‐genomic replicons.

Results

Honokiol had strong antiviral effect against HCVcc infection at non‐toxic concentrations. Combined with interferon‐α, its inhibitory effect on HCVcc was more profound than that of ribavirin. Honokiol inhibited the cell entry of lentiviral particles pseudo‐typed with glycoproteins from HCV genotypes 1a, 1b, and 2a, but not of the vesicular stomatitis virus. It had inefficient activity on HCV internal ribosome entry site (IRES)‐translation at concentrations with significant anti‐HCVcc effects. The expression levels of components of replication complex, NS3, NS5A and NS5B, were down‐regulated by honokiol in a dose‐dependent manner. It also inhibited HCV replication dose dependently in both genotypes 1b and 2a sub‐genomic replicons.

Conclusions

Honokiol inhibits HCV infection by targeting cell entry and replication and, only at a concentration >30 μM, IRES‐mediated translation of HCV life cycle. Based on its high therapeutic index (LD50/EC90 = 5.4), honokiol may be a promising drug for the treatment of HCV infection.
Bayesian Adaptive Trial Design for a Newly Validated Surrogate Endpoint
Authors: Renfro Lindsay A. , Carlin Bradley P. , Sargent Daniel J.
Published: August 2011

Summary The evaluation of surrogate endpoints for primary use in future clinical trials is an increasingly important research area, due to demands for more efficient trials coupled with recent regulatory acceptance of some surrogates as ‘valid.’ However, little consideration has been given to how a trial that utilizes a newly validated surrogate endpoint as its primary endpoint might be appropriately designed. We propose a novel Bayesian adaptive trial design that allows the new surrogate endpoint to play a dominant role in assessing the effect of an intervention, while remaining realistically cautious about its use. By incorporating multitrial historical information on the validated relationship between the surrogate and clinical endpoints, then subsequently evaluating accumulating data against this relationship as the new trial progresses, we adaptively guard against an erroneous assessment of treatment based upon a truly invalid surrogate. When the joint outcomes in the new trial seem plausible given similar historical trials, we proceed with the surrogate endpoint as the primary endpoint, and do so adaptively—perhaps stopping the trial for early success or inferiority of the experimental treatment, or for futility. Otherwise, we discard the surrogate and switch adaptive determinations to the original primary endpoint. We use simulation to test the operating characteristics of this new design compared to a standard O’Brien–Fleming approach, as well as the ability of our design to discriminate trustworthy from untrustworthy surrogates in hypothetical future trials. Furthermore, we investigate possible benefits using patient‐level data from 18 adjuvant therapy trials in colon cancer, where disease‐free survival is considered a newly validated surrogate endpoint for overall survival.
Multiple Loci Mapping via Model‐free Variable Selection
Authors: Sun Wei , Li Lexin
Published: August 2011

Summary Despite recent flourish of proposals on variable selection, genome‐wide multiple loci mapping remains to be challenging. The majority of existing variable selection methods impose a model, and often the homoscedastic linear model, prior to selection. However, the true association between the phenotypical trait and the genetic markers is rarely known a priori, and the presence of epistatic interactions makes the association more complex than a linear relation. Model‐free variable selection offers a useful alternative in this context, but the fact that the number of markers p often far exceeds the number of experimental units n renders all the existing model‐free solutions that require n > p inapplicable. In this article, we examine a number of model‐free variable selection methods for small‐n‐large‐p regressions in the context of genome‐wide multiple loci mapping. We propose and advocate a multivariate group‐wise adaptive penalization solution, which requires no model prespecification and thus works for complex trait‐marker association, and handles one variable at a time so that works for n < p. Effectiveness of the new method is demonstrated through both intensive simulations and a comprehensive real data analysis across 6100 gene expression traits.
High‐Dimensional Heteroscedastic Regression with an Application to eQTL Data Analysis
Authors: Daye Z. John , Chen Jinbo , Li Hongzhe
Published: August 2011

Summary We consider the problem of high‐dimensional regression under nonconstant error variances. Despite being a common phenomenon in biological applications, heteroscedasticity has, so far, been largely ignored in high‐dimensional analysis of genomic data sets. We propose a new methodology that allows nonconstant error variances for high‐dimensional estimation and model selection. Our method incorporates heteroscedasticity by simultaneously modeling both the mean and variance components via a novel doubly regularized approach. Extensive Monte Carlo simulations indicate that our proposed procedure can result in better estimation and variable selection than existing methods when heteroscedasticity arises from the presence of predictors explaining error variances and outliers. Further, we demonstrate the presence of heteroscedasticity in and apply our method to an expression quantitative trait loci (eQTLs) study of 112 yeast segregants. The new procedure can automatically account for heteroscedasticity in identifying the eQTLs that are associated with gene expression variations and lead to smaller prediction errors. These results demonstrate the importance of considering heteroscedasticity in eQTL data analysis.