bluuebunny/crossref_metadata_2025 huggingface dataset:
Acts of Activism
Authors: Madison D. Soyini
Published: May 2010

This book was first published in 2010. Madison presents the neglected yet compelling and necessary story of local activists in South Saharan Africa who employ modes of performance as tactics of resistance and intervention in their day-to-day struggles for human rights. The dynamic relationship between performance and activism are illustrated in three case studies: Act One presents a battle between tradition and modernity as the bodies of African women are caught in the cross-fire. Act Two focuses on 'water democracy' as activists fight for safe, accessible public water as a human right. Act Three examines the efficacy of street performance and theatre for development in the oral histories of Ghanaian gender activists. Unique to this book is the continuing juxtaposition between the everyday performances of local activism and their staged enactments before theatre audiences in Ghana and the USA. Madison beautifully demonstrates how these disparate sites of performance cohere in the service of rights, justice, and activism.
Child Soldiers
Authors: Denov Myriam
Published: May 2010

Tragically, violence and armed conflict have become commonplace in the lives of many children around the world. Not only have millions of children been forced to witness war and its atrocities, but many are drawn into conflict as active participants. Nowhere has this been more evident than in Sierra Leone during its 11-year civil war. Drawing upon in-depth interviews and focus groups with former child soldiers of Sierra Leone's rebel Revolutionary United Front, Myriam Denov compassionately examines how child soldiers are initiated into the complex world of violence and armed conflict. She also explores the ways in which the children leave this world of violence and the challenges they face when trying to renegotiate their lives and self-concepts in the aftermath of war. The narratives of the Sierra Leonean youth demonstrate that their life histories defy the narrow and limiting portrayals presented by the media and popular discourse.
Islamic Jurisprudence in the Classical Era
Authors: Calder Norman , Gleave Robert
Published: May 2010

Norman Calder is still considered a luminary in the field of Islamic law. He was one among a handful of Western scholars who were beginning to engage with the subject. In the intervening years, much has changed, and Islamic law is now understood as fundamental to any engagement with the study of Islam, its history, and its society. In this book, Colin Imber has put together and edited four essays by Norman Calder that have never been previously published. Typically incisive, they categorize and analyze the different genres of Islamic juristic literature that was produced between the tenth and fourteenth centuries, showing what function they served both in the preservation of Muslim legal and religious traditions and in the day-to-day lives of their communities. The essays also examine the status and role of the jurists themselves and give clear answers to the controversial questions of how far Islamic law and juristic thinking changed over the centuries, and how far it was able to adapt to new circumstances.
Necessary Evils
Authors: Freeman Mark
Published: May 2010

This book is about amnesties for grave international crimes that states adopt in moments of transition or social unrest. The subject is naturally controversial, especially in the age of the International Criminal Court. The goal of this book is to reframe and revitalise the global debate on the subject and to offer an original framework for resolving amnesty dilemmas when they arise. Most literature and jurisprudence on amnesties deal with only a small subset of state practice and sidestep the ambiguity of amnesty's position under international law. This book addresses the ambiguity head on and argues that amnesties of the broadest scope are sometimes defensible when adopted as a last recourse in contexts of mass violence. Drawing on an extensive amnesty database, the book offers detailed guidance on how to ensure that amnesties extend the minimum leniency possible, while imposing the maximum accountability on the beneficiaries.
The Invention of Evening
Authors: Miller Christopher R.
Published: May 2010

Lyric poetry has long been considered an art form of timelessness, but Romantic poets became fascinated by one time above all others: evening, the threshold between day and night. Christopher R. Miller investigates the cultural background of this development. The tradition of evening poetry runs from the idyllic settings of Virgil to the urban twilights of T. S. Eliot, and flourished in the works of Coleridge, Wordsworth, Shelley and Keats. In fresh readings of familiar Romantic poems, Miller shows how evening settings enabled poets to represent the passage of time and to associate it with subtle movements of thought and perception. This leads to new ways of reading canonical works, and of thinking about the kinds of themes the lyric can express.
The Culture of Giving
Authors: Ben-Amos Ilana Krausman
Published: May 2010

An innovative study of gift-giving, informal support and charity in England between the late sixteenth and early eighteenth centuries. Ilana Krausman Ben-Amos examines the adaptation and transformation of varied forms of informal help, challenging long-held views and assumptions about the decline of voluntary giving and personal obligations in the transition from medieval to modern times. Merging historical research with insights drawn from theories of gift-giving, the book analyses practices of informal support within varied social networks, associations and groups over the entire period. It argues that the processes entailed in the Reformation, state formation and the implementation of the poor laws, as well as market and urban expansion, acted as powerful catalysts for many forms of informal help. Within certain boundaries, the early modern era witnessed the diversification, increase and invigoration, rather than the demise, of gift-giving and informal support.
Elliptic Curves and Big Galois Representations
Authors: Delbourgo Daniel
Published: May 2010

The arithmetic properties of modular forms and elliptic curves lie at the heart of modern number theory. This book develops a generalisation of the method of Euler systems to a two-variable deformation ring. The resulting theory is then used to study the arithmetic of elliptic curves, in particular the Birch and Swinnerton-Dyer (BSD) formula. Three main steps are outlined: the first is to parametrise 'big' cohomology groups using (deformations of) modular symbols. Finiteness results for big Selmer groups are then established. Finally, at weight two, the arithmetic invariants of these Selmer groups allow the control of data from the BSD conjecture. As the first book on the subject, the material is introduced from scratch; both graduate students and professional number theorists will find this an ideal introduction. Material at the very forefront of current research is included, and numerical examples encourage the reader to interpret abstract theorems in concrete cases.
Famine in a land of plenty: Plight of a rice-growing community in Java, 1883–84
Authors: Fernando M.R.
Published: May 2010

This paper is an effort to examine the dynamics of a major famine in the private domains of Indramayu and Kandanghaur in 1883–84, which was reportedly a result of drought, but a closer look at the evidence, including a unique survey of peasant families engulfed in the famine, reveals a rather complex situation. The local peasantry confined to a narrow subsistence economy found its food supply being seriously undermined by the landlords' efforts to extract more and more rice for sale at a time when Java was being closely drawn into the world market.
A traffic in Songket: Translocal Malay identities in Sambas
Authors: Mee Wendy
Published: May 2010

This paper uses the example of songket to explore translocal Malay cultural processes in Sambas, West Kalimantan. I argue these intra-Malay cultural exchanges reframe selected Sambas Malay cultural forms as Malay ‘cultural heritage’, making it difficult to view cultural practices in purely localised terms. Consequently, many cultural forms lose their localised normative values and become aspects of a wider cultural heritage to be preserved, performed and consumed. The paper begins with a discussion of the historical, political and social grounds that forge a sense of translocalism amongst many Sambas Malays. Building on this, the more specific interest in participating in intra-regional Malay cultural exchanges is explained with reference to commodification, internationalisation and institutionalisation.
Hearing Voices in a Non-Psychiatric Population
Authors: Lawrence Catherine , Jones Jason , Cooper Myra
Published: May 2010

Background: Many people hear voices but do not access psychiatric services and their experiences are largely unknown, not least because of the difficulty in contacting such people. This study investigates the beliefs held about voices, distress experienced, and provides a topographical account of the experience of hearing voices in a sample of individuals who hear voices in a non-psychiatric population. Method: A quantitative questionnaire internet-based study with a within-subjects and between-subjects design was used. The internet was used to make contact with people who hear voices. One hundred and eighty-four participants in the general population who heard voices completed measures online assessing anxiety, depression, and beliefs about their dominant voice. Results: Participants reported a broad range of experiences associated with hearing voices, some in keeping with the previous research on clinical populations. Conclusion: The use of the internet to recruit and research non-clinical samples of people who hear voices is supported. This study provides details regarding demographic information and the experience of voice hearing from a fairly large sample of people who hear voices in a non-psychiatric population. It lends support to the idea that voice hearing occurs on a continuum, with evidence that many people hear voices in the general population and are not distressed by the experience.
The Time of Our Lives
Authors: Mellor D. H.
Published: May 2010

Early last century an article appeared which transformed the philosophy of time. The article was James Ellis McTaggart's ‘The unreality of time’, published in 1908. As his title implies, McTaggart argued in this article that there is in reality no such thing as time. But that claim, although startling enough, is not what makes the article so remarkable. The same claim had after all been made long before McTaggart, for example by Kant in 1781, and in McTaggart's sense it is still made by those who think that time is merely one of the four dimensions of an unchanging ‘block universe’. However, most of those who think this are more influenced by Minkowski's comment, also made in 1908, that relativity has doomed space and time to ‘fade away into mere shadows’ of a unified spacetime than they are by McTaggart's more substantial arguments.
Active Powers and Powerful Actors
Authors: Harré Rom
Published: May 2010

The usual context for raising the issue of ‘agent-causation’ is that of human action. Cf. the excellent recent book by Fred Vollmer (1999). And a long list of articles. The motivation for mounting a defence of the propriety of agent causation might be to restore moral concepts to a place in human life, via responsibility of actors for their actions, threatened by event (internal or external) causality explanation formats.
Flow: architecture, object and relation
Authors: Smith Chris L. , Ballantyne Andrew
Published: May 2010

This paper – like those following it in this issue of arq – focuses on the shifting notion of ‘flow’ and the significance of that notion for the practice, critique and theorisation of architecture.
Flows from early Modernism into the Interior Streets of Venturi, Rauch and Scott Brown
Authors: Theunissen Karin
Published: May 2010

In 1972 the famous diagram of the ‘Decorated Shed’ was introduced into the architectural discourse; it implied a definition of ‘architecture as shelter with decoration on it’ [1]. The diagram was part of urban research into the commercial environment of Las Vegas that was interpreted by the researchers – Robert Venturi, Denise Scott Brown and Steven Izenour – as ‘a new type of urban form’ that they meant ‘to understand’ in order ‘to begin to evolve techniques for its handling’. Yet the critique on this and other research and designs by Venturi, Rauch and Scott Brown focused essentially on questions of form and more specifically of the image of architecture.
Factors related to obesity among Iranian men: results from the National Health Survey
Authors: Bakhshi Enayatollah , Mohammad Kazem , Eshraghian Mohammad R , Seifi Behjat
Published: May 2010

Objective

To our knowledge, only a few Iranian studies have investigated factors associated with obesity among men. The aims of the present study were to explore the associations between sociodemographic factors, smoking and obesity in Iranian men and compare these associations between Iranian men and women.

Design

We used data from the National Health Survey in Iran. A generalised estimating equations model included 11 697 men and 14 854 women aged 20–69 years (12 850 households). Body weight and height were objectively measured. BMI was calculated as kg/m2, and subjects were classified into obese (BMI ≥ 30 kg/m2) and non-obese (BMI < 30 kg/m2).

Results

Among men, adjusted obesity OR were 0·62 (95 % CI 0·52, 0·74), 1·09 (95 % CI 0·90, 1·32), 1·003 (95 % CI 1·00, 1·007) and 0·57 (95 % CI 0·40, 0·81) for smokers, married, economic index and active workforce groups, respectively. Using low education as the reference group, the obesity OR for men were 1·06 (95 % CI 0·89, 1·26) and 0·75 (95 % CI 0·57, 0·99) for the moderate and high education groups, respectively. Using rural as the reference group, the obesity OR was 1·87 (95 % CI 1·56, 2·26) for urban men.

Conclusions

Our findings may point towards a better understanding of the social and cultural mechanisms of obesity in Iranian men. The above sociodemographic factors are large contributors to obesity and provide the greatest opportunity for actions and interventions designed for prevention and treatment.
Infant and young child feeding indicators across nine East and Southeast Asian countries: an analysis of National Survey Data 2000–2005
Authors: Dibley Michael J , Senarath Upul , Agho Kingsley E
Published: May 2010

Objective

To compare infant and young child feeding practices in children aged 0–23 months across nine East and Southeast Asian countries.

Design

Secondary analyses of cross-sectional data from available Demographic and Health Surveys (DHS; Indonesia, Philippines, Timor-Leste, Cambodia and Vietnam), Multiple Indicator Country Surveys (Lao People's Democratic Republic (Lao PDR) and Myanmar) and national nutrition surveys (Democratic People’s Republic of Korea (DPR Korea) and Mongolia) conducted between 2000 and 2005.

Setting

Seven countries from Southeast Asia and two from East Asia.

Subjects

Children aged 0–23 months with samples ranging from 826 to 5610 for DHS, and from 477 to 5860 for non-DHS data.

Results

More than 93 % of infants were ever breast-fed, and over 75 % were currently breast-fed except in the Philippines. Timely initiation of breast-feeding varied from 32 % in Indonesia to 46 % in Timor-Leste. Exclusive breast-feeding (EBF) rate in infants under 6 months of age ranged from 11 % in Myanmar to 60 % in Cambodia. EBF rates were also low in Vietnam (15·5 %) and Lao PDR (23 %), and varied between 30 % and 40 % in Indonesia, Philippines and Timor-Leste. The proportion of infants under 6 months of age who were given breast milk with non-milk liquids was high except in Indonesia and Timor-Leste. Bottle-feeding rates were lower in DPR Korea (3 %), Lao PDR (6 %) and Myanmar (6 %) and higher in the Philippines (49 %) and Mongolia (31 %). Timely complementary-feeding rate varied widely across countries (6–99 %).

Conclusions

All the countries studied should make greater efforts to improve timely initiation of breast-feeding and EBF for 6 months. Measures should be taken to reduce high bottle-feeding rate in the Philippines, Mongolia, Indonesia and Vietnam, and improve complementary-feeding rate in Lao PDR, Myanmar, DPR Korea and Philippines.
Developing an archaeology of African consumers
Authors: Croucher Sarah K.
Published: May 2010

I applaud Richard's article for continuing to move forwards the study of historical archaeology in African contexts. This article seems to fit within an ever-growing dynamic field of historical archaeologists who move easily between the realms of archaeological data, documentary and oral histories (e.g. Dawdy 2008; Voss 2008). As highlighted by Reid and Lane (2004a; see also contributions to Reid and Lane 2004b) it is perhaps better to conceptualize the study of historical archaeology on the African continent as a field of historical archaeologies, where pluralistic theoretical and methodological directions can be attended to, driven by a diversity of locally contextualized research agendas.
Response and responsibility (before and after the ‘facts’). Postcolonial thoughts on ethical writing
Authors: Richard François G.
Published: May 2010

Let me begin by expressing my heartfelt thanks to Sarah Croucher, Audrey Horning, Tim Insoll and Peter van Dommelen for their thoughtful comments. It is not uncommon for academic critique to be seduced by the facility ofcriticism, to draw its impulse from what, with Freud, we might call the ‘narcissism of small differences’, and proceed with the obstinacy of the hatchet headed for the jugular . . . More artful, and far more difficult, is a form of engagement that gives more than it takes, that disputes but in the spirit of generous exchange. I feel that the respondents have accomplished precisely that. They have crafted a space of ‘hospitable’ discussion (cf. Derrida 2000), which rests on a double movement of ‘interruption’ (Westmoreland 2008): of their plane of thoughts, by bringing my article within the ambit of their conversations; and of my ideas, by making them a little less self-evident, a little less ‘at home’. This act of ‘making strange’ – when one's viewpoints acquire a different face as they are presented anew through the minds of others – is the cloth of which constructive dialogue is made.
From theory to empirical research
Authors: Ulf Christoph
Published: May 2010

Sofia Voutsaki has developed a very stimulating line of thought in her paper. In my view, one of the laudable traits of this paper is that it is characterized by the same tripartite structure which actually lies behind each scientific argument. Consciously or not, all of us start with a theory or a set of assumptions; we then proceed to methods in order to achieve our goal, i.e. to arrive at transparent interpretations of the past through empirical analysis. The analysis of empirical data is the end of the process, not its starting point, even if many people think it would be the beginning of our daily research work. The claim that the use of theory is unavoidable is often denied. Sofia Voutsaki's goal, as I understand it, is to make an attempt to narrow the gap between, on the one hand, mainly theory-driven research and, on the other, empirical analysis which is thought to be free from the unnecessary ‘burden’ of theory.
The Value of Online Networks of Practice: The Role of Embeddedness and Media Use
Authors: van den Hooff Bart , de Leeuw van Weenen Femke , Soekijad Maura , Huysman Marleen
Published: May 2010

This article addresses the question how networks of practice (NoPs) can create value (operationalized as their contribution to individual members’ performance) for organizations through knowledge integration and management. The discussion focuses on two sets of variables influencing member performance: the embeddedness of the network and the use of different media. Three dimensions of embeddedness are distinguished: (1) embeddedness in practice: the extent to which the knowledge shared in the network is integrated in members’ (local) practices; (2) structural embeddedness: the extent to which network members are connected to each other and know who knows what; and (3) relational embeddedness: the extent to which the network is characterized by strong social ties. In terms of communication media, information and communication technology (ICT)-enabled and face-to-face interaction are distinguished. A survey study among 206 members of different NoPs reveals that all three forms of embeddedness are important antecedents of NoP member performance (explaining 43% of the variance in performance) and that these forms are interrelated. Furthermore, ICT use positively influences embeddedness in practice, whereas face-to-face communication contributes to the structural and relational embeddedness of an NoP. This contributes to knowledge management and ICT literature in general and NoP theory in particular.
The Development of Locomotor Planning for End-State Comfort
Authors: Cowie Dorothy , Smith Liam , Braddick Oliver
Published: May 2010

Walking through real-world environments involves using perceptual information to make complex choices between alternative routes, and this ability must develop through childhood. We examined performance and its development in one such situation. We used a novel ‘river-crossing’ paradigm analogous to manual ‘end-state comfort’ planning tasks, where an uncomfortable manoeuvre at the start of a movement is traded off for comfort at its end. Adults showed locomotor end-state comfort planning, adjusting feet at the start of a route in order to gain comfort at its end (crossing a manageable gap between two stepping stones). 3–6-year-olds also made this trade-off, but to a lesser degree than adults. The results suggest that end-state comfort is an important determiner of locomotor behaviour. Furthermore, they show that children as young as 3 years can use detailed visual information to form sophisticated locomotor plans.
AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality
Authors: Christie Louisa A. , Russell Theron A. , Xu Jian , Wood Lydia , Shepherd Gordon M. G. , Contractor Anis
Published: May 2010

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate) recep-tors desensitize rapidly and completely in the continued presence of their endogenous ligand glutamate; however, it is not clear what role AMPA receptor desensitization plays in the brain. We generated a knock-in mouse in which a single amino acid residue, which controls desensitization, was mutated in the GluA2 (GluR2) receptor subunit (GluA2
L483Y
). This mutation was homozygous lethal. However, mice carrying a single mutated allele, GluA2
L483Y/wt
, survived past birth, but displayed severe and progressive neurological deficits including seizures and, ultimately, increased mortality. The expression of the AMPA receptor subunits GluA1 and GluA2 was decreased, whereas NMDA receptor protein expression was increased in GluA2
L483Y/wt
mice. Despite this, basal synaptic transmission and plasticity in the hippocampus were largely unaffected, suggesting that neurons preferentially target receptors to synapses to normalize synaptic weight. We found no gross neuroanatomical alterations in GluA2
L483Y/wt
mice. Moreover, there was no accumulation of AMPA receptor subunits in intracellular compartments, suggesting that folding and assembly of AMPA receptors are not affected by this mutation. Interestingly, EPSC paired pulse ratios in the CA1 were enhanced without a change in synaptic release probability, demonstrating that postsynaptic receptor properties can contribute to facilitation. The dramatic phenotype observed in this study by the introduction of a single amino acid change demonstrates an essential role in vivo for AMPA receptor desensitization.
Endogenous retinoic acid regulates cardiac progenitor differentiation
Authors: Lin Song-Chang , Dollé Pascal , Ryckebüsch Lucile , Noseda Michela , Zaffran Stéphane , Schneider Michael D. , Niederreither Karen
Published: May 2010

Retinoic acid (RA) has several established functions during cardiac development, including actions in the fetal epicardium required for myocardial growth. An open question is if retinoid effects are limited to growth factor stimulation pathway(s) or if additional actions on uncommitted progenitor/stem populations might drive cardiac differentiation. Here we report the dual effects of RA deficiency on cardiac growth factor signaling and progenitor/stem biology using the mouse retinaldehyde dehydrogenase 2 (
Raldh2
) knockout model. Although early heart defects in
Raldh2
−/−
embryos result from second-heart-field abnormalities, it is unclear whether this role is transient or whether RA has sustained effects on cardiac progenitors. To address this, we used transient maternal RA supplementation to overcome early
Raldh2
−/−
lethality. By embryonic day 11.5–14.5,
Raldh2
−/−
hearts exhibited reduced venticular compact layer outgrowth and altered coronary vessel development. Although reductions in
Fgf2
and target pERK levels occurred, no alterations in Wnt/β-catenin expression were observed. Cell proliferation is increased in compact zone myocardium, whereas cardiomyocyte differentiation is reduced, alterations that suggest progenitor defects. We report that the fetal heart contains a reservoir of stem/progenitor cells, which can be isolated by their ability to efflux a fluorescent dye and that retinoid signaling acts on this fetal cardiac side population (SP).
Raldh2
−/−
hearts display increased SP cell numbers, with selective increases in expression of cardiac progenitor cell markers and reduced differentiation marker levels. Hence, although lack of RA signaling increases cardiac SP numbers, simultaneous reductions in Fgf signaling reduce cardiomyocyte differentiation, possibly accounting for long-term defects in myocardial growth.
SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling
Authors: Holloway Kimberly R. , Calhoun Tara N. , Saxena Madhurima , Metoyer Cheynita F. , Kandler Ethan F. , Rivera Chantal A. , Pruitt Kevin
Published: May 2010

Sirtuin 1 (SIRT1) is a class III histone deacetylase that deacetylates histone and nonhistone proteins to regulate gene transcription and protein function. Because SIRT1 regulates very diverse responses such as apoptosis, insulin sensitivity, autophagy, differentiation, and stem cell pluripotency, it has been a challenge to reconcile how it orchestrates such pleiotropic effects. Here we show that SIRT1 serves as an important regulator of Wnt signaling. We demonstrate that SIRT1 loss of function leads to a significant decrease in the levels of all three Dishevelled (Dvl) proteins. Furthermore, we demonstrate that SIRT1 and Dvl proteins complex in vivo and that inhibition of SIRT1 leads to changes in gene expression of Wnt target genes. Finally, we demonstrate that Wnt-stimulated cell migration is inhibited by a SIRT1 inhibitor. Because the three mammalian Dvl proteins serve as key messengers for as many as 19 Wnt ligands, SIRT1-mediated regulation of Dvl proteins may explain the diverse physiological responses observed in different cellular contexts. Previously, SIRT1 had only been shown to mediate the epigenetic silencing of Wnt antagonists. In contrast, here we report that SIRT1 regulates Dvl protein levels and Wnt signaling in several cellular contexts. These findings demonstrate that SIRT1 is a regulator of transient and constitutive Wnt signaling.
Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth
Authors: Murray Brion W. , Guo Chuangxing , Piraino Joseph , Westwick John K. , Zhang Cathy , Lamerdin Jane , Dagostino Eleanor , Knighton Daniel , Loi Cho-Ming , Zager Michael , Kraynov Eugenia , Popoff Ian , Christensen James G. , Martinez Ricardo , Kephart Susan E. , Marakovits Joseph , Karlicek Shannon , Bergqvist Simon , Smeal Tod
Published: May 2010

Despite abundant evidence that aberrant Rho-family GTPase activation contributes to most steps of cancer initiation and progression, there is a dearth of inhibitors of their effectors (e.g., p21-activated kinases). Through high-throughput screening and structure-based design, we identify PF-3758309, a potent (K
d
= 2.7 nM), ATP-competitive, pyrrolopyrazole inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC
50
= 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC
50
= 4.7 ± 3 nM). The molecular underpinnings of PF-3758309 biological effects were characterized using an integration of traditional and emerging technologies. Crystallographic characterization of the PF-3758309/PAK4 complex defined determinants of potency and kinase selectivity. Global high-content cellular analysis confirms that PF-3758309 modulates known PAK4-dependent signaling nodes and identifies unexpected links to additional pathways (e.g., p53). In tumor models, PF-3758309 inhibits PAK4-dependent pathways in proteomic studies and regulates functional activities related to cell proliferation and survival. PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC
50
value of 0.4 nM in the most sensitive model. This study defines PAK4-related pathways, provides additional support for PAK4 as a therapeutic target with a unique combination of functions (apoptotic, cytoskeletal, cell-cycle), and identifies a potent, orally available small-molecule PAK inhibitor with significant promise for the treatment of human cancers.
Structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca
2+
-dependent regulation of polycystin-2 channel activity
Authors: Petri Edward T. , Ćelić Andjelka , Kennedy Scott D. , Ehrlich Barbara E. , Boggon Titus J. , Hodsdon Michael E.
Published: May 2010

The C-terminal cytoplasmic tail of polycystin-2 (PC2/TRPP2), a Ca
2+
-permeable channel, is frequently mutated or truncated in autosomal dominant polycystic kidney disease. We have previously shown that this tail consists of three functional regions: an EF-hand domain (PC2-EF, 720–797), a flexible linker (798–827), and an oligomeric coiled coil domain (828–895). We found that PC2-EF binds Ca
2+
at a single site and undergoes Ca
2+
-dependent conformational changes, suggesting it is an essential element of Ca
2+
-sensitive regulation of PC2 activity. Here we describe the NMR structure and dynamics of Ca
2+
-bound PC2-EF. Human PC2-EF contains a divergent non-Ca
2+
-binding helix-loop-helix (HLH) motif packed against a canonical Ca
2+
-binding EF-hand motif. This HLH motif may have evolved from a canonical EF-hand found in invertebrate PC2 homologs. Temperature-dependent steady-state NOE experiments and NMR
R
1
and
R
2
relaxation rates correlate with increased molecular motion in the EF-hand, possibly due to exchange between apo and Ca
2+
-bound states, consistent with a role for PC2-EF as a Ca
2+
-sensitive regulator. Structure-based sequence conservation analysis reveals a conserved hydrophobic surface in the same region, which may mediate Ca
2+
-dependent protein interactions. We propose that Ca
2+
-sensing by PC2-EF is responsible for the cooperative nature of PC2 channel activation and inhibition. Based on our results, we present a mechanism of regulation of the Ca
2+
dependence of PC2 channel activity by PC2-EF.
Ohnologs in the human genome are dosage balanced and frequently associated with disease
Authors: Makino Takashi , McLysaght Aoife
Published: May 2010

About 30% of protein-coding genes in the human genome are related through two whole genome duplication (WGD) events. Although WGD is often credited with great evolutionary importance, the processes governing the retention of these genes and their biological significance remain unclear. One increasingly popular hypothesis is that dosage balance constraints are a major determinant of duplicate gene retention. We test this hypothesis and show that WGD-duplicated genes (ohnologs) have rarely experienced subsequent small-scale duplication (SSD) and are also refractory to copy number variation (CNV) in human populations and are thus likely to be sensitive to relative quantities (i.e., they are dosage-balanced). By contrast, genes that have experienced SSD in the vertebrate lineage are more likely to also display CNV. This supports the hypothesis of biased retention of dosage-balanced genes after WGD. We also show that ohnologs have a strong association with human disease. In particular, Down Syndrome (DS) caused by trisomy 21 is widely assumed to be caused by dosage effects, and 75% of previously reported candidate genes for this syndrome are ohnologs that experienced no other copy number changes. We propose the remaining dosage-balanced ohnologs on chromosome 21 as candidate DS genes. These observations clearly show a persistent resistance to dose changes in genes duplicated by WGD. Dosage balance constraints simultaneously explain duplicate gene retention and essentiality after WGD.
The M
3
-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner
Authors: Poulin Benoit , Butcher Adrian , McWilliams Phillip , Bourgognon Julie-Myrtille , Pawlak Robert , Kong Kok Choi , Bottrill Andrew , Mistry Sharad , Wess Jürgen , Rosethorne Elizabeth M. , Charlton Steven J. , Tobin Andrew B.
Published: May 2010

Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M
1
-muscarinic receptor subtype. However, recent studies have cast doubt on whether this is the primary receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M
3
-muscarinic receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M
3
-muscarinic receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M
3
-muscarinic receptor in this process involves receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient receptor mutant also shows a deficit in fear conditioning. Consistent with a role for receptor phosphorylation, we demonstrate that the M
3
-muscarinic receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M
3
-muscarinic receptor was coupled normally to G
q/11
-signaling but was uncoupled from phosphorylation-dependent processes such as receptor internalization and arrestin recruitment. It can, therefore, be concluded that M
3
-muscarinic receptor–dependent learning and memory depends, at least in part, on receptor phosphorylation/arrestin signaling. This study opens the potential for biased M
3
-muscarinic receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.
MLV glycosylated-Gag is an infectivity factor that rescues Nef-deficient HIV-1
Authors: Pizzato Massimo
Published: May 2010

Optimal infectivity of HIV-1 virions requires synthesis of the HIV-1 regulatory protein Nef in some producer cells but not others. A survey of 18 lymphoid cell lines found that Nef was dispensable in three, each of which harbored gammaretroviruses. Nef-dependent cell lines were rendered Nef-independent by a cell-free supernatant from the independent lines or by transfection of cloned murine leukemia virus (MLV). Analysis of MLV deletion mutations identified glycosylated gag (glycogag) as the factor that rescues Nef-defective HIV-1 virions. Glycogag was also demonstrated to be required for the infectivity of MLV virions produced in lymphoid cells. Direct comparison of Nef and glycogag revealed identical dependence for activity on Env-pseudotype and producer cell type. The two proteins colocalize within cells, and both increase the yield of viral cDNA in target cells. The functional similarity of Nef and glycogag is a compelling example of convergent evolution in which two structurally unrelated proteins provide a function necessary for virion infectivity in lymphoid cells.
Mapping the information flow from one brain to another during gestural communication
Authors: Schippers Marleen B. , Roebroeck Alard , Renken Remco , Nanetti Luca , Keysers Christian
Published: May 2010

Both the putative mirror neuron system (pMNS) and the ventral medial prefrontal cortex (vmPFC) are deemed important for social interaction: the pMNS because it supposedly “resonates” with the actions of others, the vmPFC because it is involved in mentalizing. Strictly speaking, the resonance property of the pMNS has never been investigated. Classical functional MRI experiments have only investigated whether pMNS regions augment their activity when an action is seen or executed. Resonance, however, entails more than only “going on and off together”. Activity in the pMNS of an observer should continuously follow the more subtle changes over time in activity of the pMNS of the actor. Here we directly explore whether such resonance indeed occurs during continuous streams of actions. We let participants play the game of charades while we measured brain activity of both gesturer and guesser. We then applied a method to localize directed influences between the brains of the participants: between-brain Granger-causality mapping. Results show that a guesser's brain activity in regions involved in mentalizing and mirroring echoes the temporal structure of a gesturer's brain activity. This provides evidence for resonance theories and indicates a fine-grained temporal interplay between regions involved in motor planning and regions involved in thinking about the mental states of others. Furthermore, this method enables experiments to be more ecologically valid by providing the opportunity to leave social interaction unconstrained. This, in turn, would allow us to tap into the neural substrates of social deficits such as autism spectrum disorder.
Simulation of cell motility that reproduces the force–velocity relationship
Authors: Schreiber Christian H. , Stewart Murray , Duke Thomas
Published: May 2010

Many cells crawl by extending an actin-rich pseudopod. We have devised a simulation that describes how the polymerization kinetics of a branched actin filament network, coupled with excluded volume effects, powers the motility of crawling cells such as amoebae and fish keratocytes. Our stochastic simulation is based on the key fundamental properties of actin polymerization, namely growth, shrinkage, capping, branching, and nucleation, and also includes contributions from the creation and breaking of adhesive contacts with the substrate together with excluded volume effects related to filament packing. When reasonable values for appropriate constants were employed, this simulation generated a force–velocity relationship that resembled closely that observed experimentally. Our simulations indicated that excluded volume effects associated with actin filament branching lead to a decreased packing efficiency and resultant swelling of the cytoskeleton gel that contributes substantially to lamellipod protrusion.
Bombykol receptors in the silkworm moth and the fruit fly
Authors: Syed Zainulabeuddin , Kopp Artyom , Kimbrell Deborah A. , Leal Walter S.
Published: May 2010

Male moths are endowed with odorant receptors (ORs) to detect species-specific sex pheromones with remarkable sensitivity and selectivity. We serendipitously discovered that an endogenous OR in the fruit fly,Drosophila melanogaster, is highly sensitive to the sex pheromone of the silkworm moth, bombykol. Intriguingly, the fruit fly detectors are more sensitive than the receptors of the silkworm moth, although its ecological significance is unknown. By expression in the “empty neuron” system, we identified the fruit fly bombykol-sensitive OR as DmelOR7a (= DmOR7a). The profiles of this receptor in response to bombykol in the native sensilla (ab4) or expressed in the empty neuron system (ab3 sensilla) are indistinguishable. Both WT and transgenic flies responded with high sensitivity, in a dose-dependent manner, and with rapid signal termination. In contrast, the same empty neuron expressing the moth bombykol receptor, BmorOR1, demonstrated low sensitivity and slow signal inactivation. When expressed in the trichoid sensilla T1 of the fruit fly, the neuron housing BmorOR1 responded with sensitivity comparable to that of the native trichoid sensilla in the silkworm moth. By challenging the native bombykol receptor in the fruit fly with high doses of another odorant to which the receptor responds with the highest sensitivity, we demonstrate that slow signal termination is induced by overdose of a stimulus. As opposed to the empty neuron system in the basiconic sensilla, the structural, biochemical, and/or biophysical features of the sensilla make the T1 trichoid system of the fly a better surrogate for the moth receptor.
A defectiveIl15allele underlies the deficiency in natural killer cell activity in nonobese diabetic mice
Authors: Suwanai Hirotsugu , Wilcox Martha Angela , Mathis Diane , Benoist Christophe
Published: May 2010

The nonobese diabetic (NOD) mouse strain has a genetic deficiency in natural killer (NK) cells. This defect underlies this strain's utility in several experimental settings; in particular, it promotes engraftment of human tissue in NOD hosts during the generation of “humanized” mouse models. We have mapped the major NK-cell defect in the NOD vs. C57BL/6 (B6) strain to an inadequately expressedIl15allele. Treatment of NOD mice with a reagent that specifically enhances interleukin (IL)-15 bioavailability normalized NK-cell numbers and activity in the absence of nonspecific stimulation. These findings raise the possibility of exploiting reagents that impact the IL-15 receptor pathway to facilitate construction of humanized mouse models on non-NOD genetic backgrounds.
Peripheral T cell lymphoma: new model + new insight
Authors: Mulloy James C.
Published: May 2010

The nonreceptor tyrosine kinase SYK has recently received a good deal of attention as a critical oncogene in various hematologic malignancies. A newly developed model of peripheral T cell lymphoma (PTCL) using the ITK-SYK fusion gene should serve as a powerful tool to dissect the signaling cascades important for SYK-associated malignancy in the context of t(5;9) PTCL.
Affinity measured by microcluster
Authors: Fooksman David R. , Dustin Michael L.
Published: May 2010

Like T cell activation, B cell activation is driven by aggregation of B cell receptors (BCRs) into microclusters. New work suggests that the early dynamics of BCR mobility and microcluster formation “translate” BCR affinity for antigen into B cell responsiveness.
Antioxidant and Anti‐Cancer Potentials of Rheum emodi Rhizome Extracts
Authors: Rajkumar Venkatadri , Guha Gunjan , Ashok Kumar Rangasamy
Published: May 2010

The objective of this study was to determine antioxidant and cytotoxic efficacies of methanolic and aqueous extracts of Rheum emodi Wall. ex Meissn. rhizome. 2,2‐Diphenyl‐1‐picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities, inhibitory effect on lipid peroxidation and Fe3+ reducing antioxidant property have been used to investigate antioxidant properties of the extracts. Cytotoxicity of the extracts was tested on MDA‐MB‐435S and Hep3B cell lines. Both extracts displayed extensive cytotoxicity to the tested cell lines. The extracts were studied for their ability to protect pBR322 DNA from damage by UV induced photolysis of H2O2. The aqueous extract, though inferior to methanolic extract in its antioxidant potential exhibited efficiency in DNA protection, while the methanolic extract failed to protect the DNA. The amount of total polyphenolics in the extracts was measured by spectrophotometric method. The methanolic extract contained higher polyphenolic contents than aqueous extract. Significant positive correlations were observed (P < .05) between results of phenolic content estimation and that of antioxidant assays. Hence, high‐performance liquid chromatography analysis was performed to identify few major phenolic compounds that might be responsible for these therapeutic properties. These results indicate that rhizome of R. emodi possesses antioxidant and cytotoxic activities and therefore have therapeutic potential.
Who needs colonoscopy to identify colorectal cancer? Bowel symptoms do not add substantially to age and other medical history
Authors: Adelstein B.‐A. , Irwig L. , Macaskill P. , Turner R. M. , Chan S. F. , Katelaris P. H.
Published: May 2010

Aliment Pharmacol Ther 2010; 32: 270–281

Background  Many bodies advise that people with bowel symptoms undergo colonoscopy to detect colorectal cancer.

Aim  To determine which bowel symptoms predict cancer on colonoscopy.

Methods  Information was collected on symptoms, demographics and medical history from patients subsequently undergoing colonoscopy. Multiple logistic regression modelling was used to identify predictors of colorectal cancer. An ROC curve was estimated for each model, and the area under the curve (AUC) was computed.

Results  Cancer was found in 159 patients and no cancer or adenoma in 7577 patients. Bowel symptoms that predicted cancer were rectal bleeding, change in bowel habit and rectal mucus. Prediction was the strongest in patients who had symptoms at least weekly and commencing within the previous 12 months; abdominal pain was predictive only in such patients. The odds ratios never exceeded 4.27. A model based on age, gender, and medical history was highly predictive (AUC = 0.79). Adding symptoms to this model increased the AUC to 0.85.

Conclusions  This model predicts patients in whom colonoscopy will have the highest yield. Conversely, colonoscopy can be avoided in people at low risk: in our study, 95% of cancers could have been detected by doing only 60% of the colonoscopies.