bluuebunny/crossref_metadata_2025 huggingface dataset:
Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review
Authors: Whale R. , Terao T. , Cowen P. , Freemantle N. , Geddes J.
Published: October 2008

Adding pindolol to serotonergic antidepressant treatment offers a potential strategy for producing a more rapid onset of action and an enhanced antidepressant effect. This review investigated whether pindolol enhances the efficacy of serotonergic antidepressant treatment in adult patients with depressive disorders at sequential time points up to 6 weeks. Search strategy: Cochrane Collaboration Depression, Anxiety and Neurosis-Controlled Trials Register plus unpublished trial data. Study selection: Randomised trials including depressed patients, comparing serotonergic antidepressants + pindolol with serotonergic antidepressants + placebo and using depressive symptom clinical outcomes scales. Data extraction: Clinical response at time points up to 6 weeks as defined by >50% depression scale score reduction was extracted for each trial as possible. Eleven studies were identified including unpublished data. The pooled odds ratios for dichotomous response to treatment at time points from 1 to 6 weeks were 2.39 (95% CI 1.40—4.06), 2.39 (1.74—3.29), 1.94 (1.46—2.58), 1.59 (1.16—2.18), 1.42 (0.87—2.31) and 1.28 (0.91—1.81). Time-to-event analysis showed a greater response with pindolol augmentation versus placebo (P = 0.04). There was significant heterogeneity between studies at some time points. Dropout rates did not significantly differ between treatment arms. This review suggests an overall beneficial clinical effect of pindolol augmentation, most clearly up to 4 weeks of treatment.
The effects of single dose anxiolytic medication on the CO2 models of anxiety: differentiation of subjective and objective measures
Authors: Papadopoulos A. , Rich A. , Nutt DJ , Bailey JE
Published: October 2008

This was a double blind, placebo-controlled, 4-way cross-over study in 12 healthy volunteer subjects of the acute effects of three drugs each of which are used in the clinic to treat some forms of anxiety: propranolol 40 mg, hydroxyzine 25 mg, flupentixol 0.5 mg and placebo. Each test session consisted of inhalation of air for 20 min, 10-min rest, inhalation of CO2 7.5% for 20 min, 10-min rest, followed by a single vital capacity inhalation of 35% CO2. The CO2 7.5% was administered at peak drug effect. Subjective effects were measured using Visual Analogue Scales (VAS), the Panic Symptom Inventory and the Generalised Anxiety Disorder Assessment inventory. Twelve subjects participated (eight men), with a mean age of 25.9 years. The expected subjective effects of CO2 were seen and these were significantly different from effects of peak air. However, there were no statistically significant differences between the drugs or between drugs and placebo, indeed there was a trend for some VAS anxiety Email: Jayne.Bailey@bristol.ac.uk scores to be higher than placebo in the drug groups. There were some significant differences in cardiovascular responses to CO2, with propranolol significantly decreasing heart rate and flupentixol increasing blood pressure when compared with placebo. The lack of subjective anxiolytic actions of the three drugs contrasts with our previous findings with acute benzodiazepines and chronic selective serotonin reuptake inhibitor administration. It may be that prolonged treatment with these agents would be required to show anxiolytic effects, although it may also be that their efficacy is insufficient to be demonstrated in this model. The lack of anxiolytic actions of propranolol, despite a significant reduction in heart rate, is a further support for a central action of CO2 to produce anxiety.
Propranolol transiently inhibits reinstatement of nicotine-seeking behaviour in rats
Authors: Chiamulera C. , Tedesco V. , Zangrandi L. , Giuliano C. , Fumagalli G.
Published: October 2008

Noradrenergic transmission has been implicated in the affective component of relapse to tobacco smoking. Evidence in human and laboratory animals showed that smoking or nicotine administration may cause changes of the noradrenergic system resulting in hyperactivity in this system after cessation. It has been hypothesised that the anti-adrenergic β-blocker propranolol may decrease affective activation and arousal observed during drug withdrawal or cue-induced relapse. The aim of the present work was to test the effects of propranolol pre-treatment in a rat model of nicotine cue-induced relapse to nicotine seeking. We also tested the effects of propranolol on food cue-induced reinstatement of food seeking in rats trained on food self-administration. Propranolol transiently inhibited nicotine cue-induced reinstatement. The inhibitory effect of propranolol reached a peak after 30 min from the beginning of the reinstatement session and then it declined until it was completely absent at the end of the 3-h session. This inhibitory effect of propranolol was not observed when the drug was tested versus reinstatement with food cues. The present study suggests a weak effect of propranolol to counteract nicotine cue-induced reinstatement of nicotine seeking. Therefore, these findings do not support a potential use of propranolol for prevention of smoking relapse.
Augmenting serotonin neurotransmission with citalopram modulates emotional expression decoding but not structural encoding of moderate intensity sad facial emotional stimuli: an event-related potential (ERP) investigation
Authors: Labuschagne I. , Croft RJ , Phan KL , Nathan PJ
Published: October 2008

Antidepressants targeting the serotonergic system have been shown to modulate biases in emotional processing. The effects of serotonergic modulation on the temporal course of emotional processing (accruing within milliseconds) are unknown. Furthermore, it is unknown how serotonin affects different stages of facial emotional processing. The current study investigated the effects of acute serotonin augmentation on event-related potential (ERP) measures associated with ‘structural encoding’ (N170) and emotion ‘expression decoding’ (N250 and a late slow-wave positive potential [LPP]) of happy and sad facial stimuli, relative to neutral facial stimuli. The study was a double-blind, placebo-controlled, cross-over design, in which 14 healthy male participants completed a facial recognition task under two acute treatment conditions: 1) placebo (PLB) and 2) 20 mg citalopram (CIT). ERP recording were conducted while subjects viewed neutral, happy and sad facial stimuli. Findings indicated that under PLB, the N170 was not modulated by valence (happy or sad versus neutral), but the N250 and LPP were enhanced for processing happy (relative to neutral) faces. Citalopram had no effect on the N170, but it enhanced the LPP for processing sad (relative to neutral) faces. These findings suggest that serotonin enhancement has selective and temporal effects on emotional face processing, with evidence for modulating processes associated with ‘expression decoding’ but not ‘structural encoding’. The enhanced cortical response to perception of moderately intense sad facial expressions following citalopram administration may relate to the cognitive processing of the social relevance or significance of such ambiguous stimuli.
Intimacy in research: accounting for it
Authors: Steedman Carolyn
Published: October 2008

Historical practice is described in terms of the intimacies involved in reading archival material and the fashioning of it into historical argument. Research into the domestic service relationship in 18th-century England, using household account books, underpins the historian's construction of imaginary relationships with the dead and gone. Other readers intervene in the writing process, and shape the history that is produced out of archival research.
If no means no, does yes mean yes? Consenting to research intimacies
Authors: O'Connell Davidson Julia
Published: October 2008

This article reflects on some ethical dilemmas presented by an ethnographic study of prostitution that I conducted in the 1990s. The study drew one research subject into a long and very close relationship with me, and though she was an active and fully consenting participant in the research, she was also objectified within both the field relationship and the textual products it generated. This kind of contradiction has been recognized and discussed as a more general problem for ethnography by feminist and critical ethnographers. In this article it is considered specifically in relation to informed consent as an ethical issue. If an ethnographer secures the free and informed consent of a research subject, does this necessarily make the intimacy of their subsequent relationship ethical? Is it possible for anyone to genuinely consent to being objectified through the research process?
Looking emotionally: photography, racism and intimacy in research
Authors: Moreno Figueroa Mónica G.
Published: October 2008

In this article I argue the need for a reflexive use of photographic images in research, mainly in the publication and dissemination phase and specifically when the topic investigated relates to issues of visibility, in this case racism and understandings of beauty. This analysis draws on my work on contemporary practices of racism in Mexico, where personal photographs were used as research tools in life-story interviews, creating a sense of shared intimacy. Inspired by Barthes' refusal in Camera Lucida (2000) to reproduce a photograph of his mother, in this article I focus on the dynamics between seeing and looking and suggest that `looking emotionally' at both participants' accounts and their photographic images, is a way to address the complexities of the gaze and discuss the specificity of different `ways of looking'. The notion of `looking emotionally' refers to an engagement, of researchers and audiences of research, with participants' lived emotional experiences that explicitly confronts the historical and social legacies of the visible. Here, photographs are understood not only as illustrative platforms from where experiences are organized, but also as `traps' that both inform and ensnare (Gell, 1999). As such, the argument aims to problematize the intimate relationship between gaze and photographic image in a context where racism is constrained to the visible, both in its reproduction and also in its pressing ongoing critique.
Making objective facts from intimate relations: the case of neuroscience and its entanglements with volunteers
Authors: Cohn Simon
Published: October 2008

This article explores the way in which the practice of neuroscience, in the form of contemporary brain-imaging, has to actively define and isolate aspects of mindfulness as solely contained within the individual. Although hidden from final scientific accounts, at the centre of this process is the need for the researchers to forge brief but intimate and personal relationships with the volunteers in their studies. With their increasing interest in studying more and more complex mental processes, and in particular as researchers focus on what they term `the social brain', a potential paradox arises from the commitment to the straightforward location of brain function and recognition of the more distributed and intersubjective nature of the objects of their study. Consequently, in order to elicit specific mental activities, such as empathy, the scientists inevitably employ a range of socially based resources, which includes establishing a personal relationship with the volunteers. The scientists themselves see this as ensuring that they can trust that the volunteers will participate in the ways intended. But in contrast, the article argues that the central feature is actually the creation of a sense of intimacy, which serves to align the expectations and experiences of volunteer and researcher. Yet, while this relationship is necessary in order to ensure the required mental state is generated, during the experiment itself a great deal of work is then done to ensure it can be excluded from the final conceptualization of mental activity.
Getting to the Top
Authors: Escobar-Lemmon Maria , Taylor-Robinson Michelle M.
Published: October 2008

Are presidential cabinets gendered institutions? This important question has been ignored for Latin America to date. In this article, the authors propose four benchmarks for evaluating whether presidential cabinets should be classified as gendered institutions. If they are we should observe (1) that there are differences in career length, continuity, and mobility between men and women; (2) that women receive feminine domain posts and men masculine ones; (3) that masculine ministries offer greater potential for upward mobility; and (4) that women must be better qualified than men to receive appointments. Using data from eighteen Latin American countries from 1980 to 2003, the authors analyze the degree to which cabinets conform to these criteria. They conclude that even though women are starting to gain appointments to high-profile and to masculine domain cabinet posts, the overall evidence supports the conclusion that there are gendered patterns to cabinet appointments.
Do Gender Stereotypes Transcend Party?
Authors: Sanbonmatsu Kira , Dolan Kathleen
Published: October 2008

Voters hold stereotypes about candidate gender and candidate party. Yet little is known about the intersection of gender and party stereotypes. In this article, we investigate whether gender stereotypes transcend party. We consider whether gender stereotypes affect woman politicians differently by party and examine the effect of partisan identification on gender stereotypes. We find that the public perceives gender differences within both political parties. Thus the presence of the party cue does not preclude a role for candidate gender. However, we also find that the implications of gender stereotypes are somewhat different for Democratic and Republican women.
Reconstructing the “Problem” of Race
Authors: Fong Edmund
Published: October 2008

How should the “problem” of race be conceptualized? This essay attempts to widen our understanding of the problem of race in American political discourse by examining its productive function in grounding the meaning of American liberalism. By tracing this relationship in W. E. B. DuBois's The Souls of Black Folk, Woodrow Wilson's 1913 Gettysburg Reunion Speech, Louis Hartz's The Liberal Tradition in America, and Rogers M. Smith's Civic Ideals, the author argues that as long as race is conceived as the negative referent of American liberal identity, the problem of race will continue to obscure the possibilities for transformative change.
Who Integrated Major League Baseball Faster
Authors: Hanssen F. Andrew , Meehan James W.
Published: October 2008

In this article, the authors investigate the process of racial integration in Major League Baseball, critiquing the empirical approach used by Goff, McCormick, and Tollison (GMT; 2002). GMT claim to find evidence suggesting that winners integrated fastest. This study shows that when their empirical model is properly specified, the results do not support that conclusion. Several alternative tests are employed and the evidence is inconclusive—if anything, there is some weak support for the hypothesis that losers integrate faster.
Penile Fracture Following Husband Abuse: A Case Report
Authors: Dienye Paul O. , Jebbin Nze J. , Gbeneol Precious K.
Published: October 2008

The case of a 35-year-old fisherman who presented in a rural clinic with a sudden onset of painful penile swelling affecting the left lateral side with associated rapid detumescence is reported. He had tried to coerce his wife to a sexual intercourse when she forcefully bent his penis. He was initially managed with cold applications, oral diclofenac potassium, chymoral, and splinting of the penis and then referred to the urological services of a teaching hospital. He defaulted only to re-present about 2 weeks later with some improvement in his symptoms. Further advice to see the urologist was also rebuffed on financial grounds. When he reported about 1 month later, he was assessed to have grade 3 erectile dysfunction. In conclusion, penile fracture is a rare condition which follows unphysiological bending of the tumescent penis during sexual intercourse or masturbation. That following husband abuse is rarer. The sequelae can be devastating.
Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2–dependent regulatory dendritic cell population
Authors: Zhang Bin , Liu Rui , Shi Dan , Liu Xingxia , Chen Yuan , Dou Xiaowei , Zhu Xishan , Lu Chunhua , Liang Wei , Liao Lianming , Zenke Martin , Zhao Robert C. H.
Published: October 2008

Mesenchymal stem cells (MSCs), in addition to their multilineage differentiation, exert immunomodulatory effects on immune cells, even dendritic cells (DCs). However, whether they influence the destiny of full mature DCs (maDCs) remains controversial. Here we report that MSCs vigorously promote proliferation of maDCs, significantly reduce their expression of Ia, CD11c, CD80, CD86, and CD40 while increasing CD11b expression. Interestingly, though these phenotypes clearly suggest their skew to immature status, bacterial lipopolysaccharide (LPS) stimulation could not reverse this trend. Moreover, high endocytosic capacity, low immunogenicity, and strong immunoregulatory function of MSC-treated maDCs (MSC-DCs) were also observed. Furthermore we found that MSCs, partly via cell-cell contact, drive maDCs to differentiate into a novel Jagged-2–dependent regulatory DC population and escape their apoptotic fate. These results further support the role of MSCs in preventing rejection in organ transplantation and treatment of autoimmune disease.
Endothelial progenitor cell homing: prominent role of the IGF2-IGF2R-PLCβ2 axis
Authors: Maeng Yong-Sun , Choi Hyun-Jung , Kwon Ja-Young , Park Yong-Won , Choi Kyu-Sil , Min Jeong-Ki , Kim Yun-Hee , Suh Pann-Ghill , Kang Kyung-Sun , Won Moo-Ho , Kim Young-Myeong , Kwon Young-Guen
Published: October 2008

Homing of endothelial progenitor cells (EPCs) to the neovascular zone is now considered to be an essential step in the formation of vascular networks during embryonic development and also for neovascularization in postnatal life. We report here the prominent role of the insulin-like growth factor 2 (IGF2)/IGF2 receptor (IGF2R) system in promoting EPC homing. With high-level expression of IGF2R in EPCs, IGF2-induced hypoxic conditions stimulated multiple steps of EPC homing in vitro and promoted both EPC recruitment and incorporation into the neovascular area, resulting in enhanced angiogenesis in vivo. Remarkably, all IGF2 actions were exerted predominantly through IGF2R-linked G(i) protein signaling and required intracellular Ca2+ mobilization induced by the β2 isoform of phospholipase C. Together, these findings indicate that locally generated IGF2 at either ischemic or tumor sites may contribute to postnatal vasculogenesis by augmenting the recruitment of EPCs. The utilization of the IGF2/IGF2R system may therefore be useful for the development of novel means to treat angiogenesis-dependent diseases.
Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation
Authors: Braun Attila , Varga-Szabo David , Kleinschnitz Christoph , Pleines Irina , Bender Markus , Austinat Madeleine , Bösl Michael , Stoll Guido , Nieswandt Bernhard
Published: October 2008

Platelet activation and aggregation at sites of vascular injury are essential for primary hemostasis, but are also major pathomechanisms underlying myocardial infarction and stroke. Changes in [Ca2+]i are a central step in platelet activation. In nonexcitable cells, receptor-mediated depletion of intracellular Ca2+ stores triggers Ca2+ entry through store-operated calcium (SOC) channels. STIM1 has been identified as an endoplasmic reticulum (ER)–resident Ca2+ sensor that regulates store-operated calcium entry (SOCE) in immune cells and platelets, but the identity of the platelet SOC channel has remained elusive. Orai1 (CRACM1) is the recently discovered SOC (CRAC) channel in T cells and mast cells but its role in mammalian physiology is unknown. Here we report that Orai1 is strongly expressed in human and mouse platelets. To test its role in blood clotting, we generated Orai1-deficient mice and found that their platelets display severely defective SOCE, agonist-induced Ca2+ responses, and impaired activation and thrombus formation under flow in vitro. As a direct consequence, Orai1 deficiency in mice results in resistance to pulmonary thromboembolism, arterial thrombosis, and ischemic brain infarction, but only mild bleeding time prolongation. These results establish Orai1 as the long-sought platelet SOC channel and a crucial mediator of ischemic cardiovascular and cerebrovascular events.
Brachyspira pilosicoli bloodstream infections: Case report and review of the literature
Authors: Bait-Merabet Lilia , Thille Arnaud , Legrand Patrick , Brun-Buisson Christian , Cattoir Vincent
Published: October 2008

Brachyspira pilosicoli is the etiologic agent of human and animal intestinal spirochetosis and is rarely implicated as a cause of bacteremia. Here, we describe the case of a B. pilosicoli spirochetemia in a 53-year-old male patient suffering from cardiogenic shock. This fastidious bacterium was isolated from blood, likely after translocation from the intestinal tract. Blood cultures were positive after 5 days of incubation (one day after the patient's death), highlighting the problem of the recovery of such type of fastidious bacterium. Identification was achieved by molecular methods (16S rRNA sequencing). A review of the English literature found only 8 cases of bacteremia caused by B. pilosicoli, mostly in immunocompromised or critically ill patients. Finally, difficulties in rapid and accurate diagnosis of B. pilosicoli bloodstream infections, in vitro antimicrobial susceptibility of human clinical isolates, and therapeutic options are discussed.
Rationale for prostaglandin I2in bone marrow oedema – from theory to application
Authors: Jäger Marcus , Tillmann Frank Peter , Thornhill Thomas S , Mahmoudi Marcus , Blondin Dirk , Hetzel Gerd Rüdiger , Zilkens Christoph , Krauspe Rüdiger
Published: October 2008

Introduction

Bone marrow oedema (BME) and avascular osteonecrosis (AVN) are disorders of unclear origin. Although there are numerous operative and non-operative treatments for AVN, pain management in patients with AVN remains challenging. Prostaglandins play an important role in inflammatory responses and cell differentiation. It is thought that prostaglandin I2 ([PGI2] or synonoma prostacyclin) and its analogues promote bone regeneration on a cellular or systemic level. The purpose of this study was to assess the curative and symptomatic efficacy of the prostacyclin analogue iloprost in BME and AVN patients.

Method

We are reporting on 50 patients (117 bones) affected by BME/AVN who were treated with iloprost. Pain levels before, during and 3 and 6 months after iloprost application were evaluated by a visual analogue scale (VAS). The short form(SF)-36 health survey served to judge general health status before and after treatment. Harris Hip Score (HHS) and Knee Society Score (KSS) were performed as functional scores and MRI and X-rays before and 3 and 6 months after iloprost application served as objective parameters for morphological changes of the affected bones.

Results

We found a significant improvement in pain, functional and radiological outcome in BME and early AVN stages after iloprost application, whereas patients with advanced AVN stages did not benefit from iloprost infusions. Mean pain level decreased from 5.26 (day 0) to 1.63 (6 months) and both HHS and KSS increased during follow-up. Moreover, the SF-36 increased from 353.2 (day 0) to 560.5 points (6 months). We found a significant decrease in BME on MRI scans after iloprost application.

Conclusions

In addition to other drugs, iloprost may be an alternative substance which should be considered in the treatment of BME/AVN-associated pain.
Notch signaling is required for the maintenance of enteric neural crest progenitors
Authors: Okamura Yoshiaki , Saga Yumiko
Published: October 2008

Notch signaling is involved in neurogenesis, including that of the peripheral nervous system as derived from neural crest cells (NCCs). However,it remains unclear which step is regulated by this signaling. To address this question, we took advantage of the Cre-loxP system to specifically eliminate the protein O-fucosyltransferase 1 (Pofut1) gene, which is a core component of Notch signaling, in NCCs. NCC-specific Pofut1-knockout mice died within 1 day of birth, accompanied by a defect of enteric nervous system (ENS) development. These embryos showed a reduction in enteric neural crest cells (ENCCs) resulting from premature neurogenesis. We found that Sox10 expression, which is normally maintained in ENCC progenitors, was decreased in Pofut1-null ENCCs. By contrast,the number of ENCCs that expressed Mash1, a potent repressor of Sox10, was increased in the Pofut1-null mouse. Given that Mash1 is suppressed via the Notch signaling pathway, we propose a model in which ENCCs have a cell-autonomous differentiating program for neurons as reflected in the expression of Mash1, and in which Notch signaling is required for the maintenance of ENS progenitors by attenuating this cell-autonomous program via the suppression of Mash1.
PDGF signalling controls the migration of mesoderm cells during chick gastrulation by regulating N-cadherin expression
Authors: Yang Xuesong , Chrisman Holly , Weijer Cornelis J.
Published: October 2008

In the early chick embryo, Pdgfa is expressed in the epiblast,outlining the migration route that mesoderm cells expressing the receptor, Pdgfrα, follow to form somites. Both expression of a dominant-negative PDGFRα and depletion of endogenous PDGFRαligands through injection of PDGFRα-Fc fragments, inhibit the migration of mesoderm cells after their ingression through the primitive streak. siRNA-mediated downregulation of Pdgfa expression in the epiblast on one side of the streak strongly blocks the migration of mesoderm cells into that side. Beads soaked in PDGFA elicit a directional attractive movement response in mesoderm cells, showing that PDGFA can provide directional information. Surprisingly, however, PDGF signalling is also required for directional movement towards other attractants, such as FGF4. PDGF signalling controls N-cadherin expression on mesoderm cells, which is required for efficient migration. PDGF signalling activates the PI3 kinase signalling pathway in vivo and activation of this pathway is required for proper N-cadherin expression.
Autonomous and non-autonomous Shh signalling mediate the in vivo growth and guidance of mouse retinal ganglion cell axons
Authors: Sánchez-Camacho Cristina , Bovolenta Paola
Published: October 2008

In non-mammalian vertebrates, the relatively homogeneous population of retinal ganglion cells (RGCs) differentiates and projects entirely to the contralateral side of the brain under the influence of sonic hedgehog (Shh). In mammals, by contrast, there are two different RGC types: the Zic2-positive ipsilateral projecting and the Isl2-positive contralateral projecting. We asked whether the axons of these two populations respond to Shh and if their response differs. We have also analysed whether midline- and RGC-derived Shh contributes to the growth of the axons in the proximal visual pathway. We show that these two RGC types are characterised by a differential expression of Shh signalling components and that they respond differently to Shh when challenged in vitro. In vivo blockade of Shh activity, however, alters the path and distribution mostly of the contralateral projecting RGC axons at the chiasm,indicating that midline-derived Shh participates in funnelling contralateral visual fibres in this region. Furthermore, interference with Shh signalling in the RGCs themselves causes abnormal growth and navigation of contralateral projecting axons in the proximal portion of the pathway, highlighting a novel cell-autonomous mechanism by which Shh can influence growth cone behaviour.
Pdm and Castor close successive temporal identity windows in the NB3-1 lineage
Authors: Tran Khoa D. , Doe Chris Q.
Published: October 2008

Neurogenesis in Drosophila and mammals requires the precise integration of spatial and temporal cues. In Drosophila, embryonic neural progenitors (neuroblasts) sequentially express the transcription factors Hunchback, Kruppel, Pdm1/Pdm2 (Pdm) and Castor as they generate a stereotyped sequence of neuronal and glial progeny. Hunchback and Kruppel specify early temporal identity in two posterior neuroblast lineages (NB7-1 and NB7-3), whereas Pdm and Castor specify late neuronal identity in the NB7-1 lineage. Because Pdm and Castor have only been assayed in one lineage, it is unknown whether their function is restricted to neuronal identity in the NB7-1 lineage, or whether they function more broadly as late temporal identity genes in all neuroblast lineages. Here, we identify neuronal birth-order and molecular markers within the NB3-1 cell lineage, and then use this lineage to assay Pdm and Castor function. We show that Hunchback and Kruppel specify first and second temporal identities, respectively. Surprisingly, Pdm does not specify the third temporal identity, but instead acts as a timing factor to close the second temporal identity window. Similarly, Castor closes the third temporal identity window. We conclude that Hunchback and Kruppel specify the first and second temporal identities, an unknown factor specifies the third temporal identity, and Pdm and Castor are timing factors that close the second and third temporal identity windows in the NB3-1 lineage. Our results provide a new neuroblast lineage for investigating temporal identity and reveal the importance of Pdm and Cas as timing factors that close temporal identity windows.
Frs2α-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis
Authors: Zhang Jue , Lin Yongshun , Zhang Yongyou , Lan Yongsheng , Lin Chunhong , Moon Anne M. , Schwartz Robert J. , Martin James F. , Wang Fen
Published: October 2008

The cardiac outflow tract (OFT) is a developmentally complex structure derived from multiple lineages and is often defective in human congenital anomalies. Although emerging evidence shows that fibroblast growth factor(FGF) is essential for OFT development, the downstream pathways mediating FGF signaling in cardiac progenitors remain poorly understood. Here, we report that FRS2α (FRS2), an adaptor protein that links FGF receptor kinases to multiple signaling pathways, mediates crucial aspects of FGF-dependent OFT development in mouse. Ablation of Frs2α in mesodermal OFT progenitor cells that originate in the second heart field (SHF) affects their expansion into the OFT myocardium, resulting in OFT misalignment and hypoplasia. Moreover, Frs2α mutants have defective endothelial-to-mesenchymal transition and neural crest cell recruitment into the OFT cushions, resulting in OFT septation defects. These results provide new insight into the signaling molecules downstream of FGF receptor tyrosine kinases in cardiac progenitors.
Functional resolution of duplicatedhoxb5genes in teleosts
Authors: Jarinova Olga , Hatch Gary , Poitras Luc , Prudhomme Christelle , Grzyb Magdalena , Aubin Josée , Bérubé-Simard Félix-Antoine , Jeannotte Lucie , Ekker Marc
Published: October 2008

The duplication-degeneration-complementation (DDC) model predicts that subfunctionalization of duplicated genes is a common mechanism for their preservation. The additional Hox complexes of teleost fish constitute a good system in which to test this hypothesis. Zebrafish have two hoxbcomplexes, with two hoxb5 genes, hoxb5a and hoxb5b,the expression patterns of which suggest subfunctionalization of an ancestral hoxb5 gene. We characterized conserved non-coding elements (CNEs)near the zebrafish hoxb5 genes. One CNE, J3, is only retained in the hoxb5a locus, whereas the others, J1 and J2, are present in both hoxb5 loci. When tested individually, the enhancer activity of individual CNEs, including J3, extensively overlapped and did not support a role in subfunctionalization. By contrast, reporter transgene constructs encompassing multiple CNEs were able to target reporter gene expression to unique domains of hoxb5a and hoxb5b expression. The deletion of J3 from the hoxb5a locus resulted in expression that approached that of hoxb5b, whereas its insertion in the hoxb5b locus increased reporter expression and rendered it more similar to that of hoxb5a. Our results highlight the importance of interactions between CNEs in the execution of complementary subfunctions of duplicated genes.
PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1α signaling and endoplasmic reticulum stress
Authors: Yang Guan , Sun Qiang , Teng Yan , Li Fangfei , Weng Tujun , Yang Xiao
Published: October 2008

Chondrocytes within the growth plates acclimatize themselves to a variety of stresses that might otherwise disturb cell fate. The tumor suppressor PTEN(phosphatase and tensin homolog deleted from chromosome 10) has been implicated in the maintenance of cell homeostasis. However, the functions of PTEN in regulating chondrocytic adaptation to stresses remain largely unknown. In this study, we have created chondrocyte-specific Pten knockout mice (Ptenco/co;Col2a1-Cre) using the Cre-loxP system. Following AKT activation, Pten mutant mice exhibited dyschondroplasia resembling human enchondroma. Cartilaginous nodules originated from Pten mutant resting chondrocytes that suffered from impaired proliferation and differentiation, and this was coupled with enhanced endoplasmic reticulum (ER) stress. We further found that ER stress in Pten mutant chondrocytes only occurred under hypoxic stress,characterized by an upregulation of unfolded protein response-related genes as well as an engorged and fragmented ER in which collagens were trapped. An upregulation of hypoxia-inducible factor 1α (HIF1α) and downstream targets followed by ER stress induction was also observed in Ptenmutant growth plates and in cultured chondrocytes, suggesting that PI3K/AKT signaling modulates chondrocytic adaptation to hypoxic stress via regulation of the HIF1α pathway. These data demonstrate that PTEN function in chondrocytes is essential for their adaptation to stresses and for the inhibition of dyschondroplasia.
Arabidopsis iba response5 Suppressors Separate Responses to Various Hormones
Authors: Strader Lucia C , Monroe-Augustus Melanie , Rogers Kristen C , Lin Grace L , Bartel Bonnie
Published: October 2008

Auxin controls numerous plant growth processes by directing cell division and expansion. Auxin-response mutants, including iba response5 (ibr5), exhibit a long root and decreased lateral root production in response to exogenous auxins. ibr5 also displays resistance to the phytohormone abscisic acid (ABA). We found that the sar3 suppressor of auxin resistant1 (axr1) mutant does not suppress ibr5 auxin-response defects, suggesting that screening for ibr5 suppressors might reveal new components important for phytohormone responsiveness. We identified two classes of Arabidopsis thaliana mutants that suppressed ibr5 resistance to indole-3-butyric acid (IBA): those with restored responses to both the auxin precursor IBA and the active auxin indole-3-acetic acid (IAA) and those with restored response to IBA but not IAA. Restored IAA sensitivity was accompanied by restored ABA responsiveness, whereas suppressors that remained IAA resistant also remained ABA resistant. Some suppressors restored sensitivity to both natural and synthetic auxins; others restored responsiveness only to auxin precursors. We used positional information to determine that one ibr5 suppressor carried a mutation in PLEIOTROPIC DRUG RESISTANCE9 (PDR9/ABCG37/At3g53480), which encodes an ATP-binding cassette transporter previously implicated in cellular efflux of the synthetic auxin 2,4-dichlorophenoxyacetic acid.
Selection for Environmental Variation: A Statistical Analysis and Power Calculations to Detect Response
Authors: Ibáñez-Escriche Noelia , Sorensen Daniel , Waagepetersen Rasmus , Blasco Agustín
Published: October 2008

Data from uterine capacity in rabbits (litter size) were analyzed to determine whether the environmental variance was partly genetically determined. The fit of a classical homogeneous variance mixed linear (HOM) model and that of a genetically structured heterogeneous variance mixed linear (HET) model were compared. Various methods to assess the quality of fit favor the HET model. The posterior mean (95% posterior interval) of the additive genetic variance affecting the environmental variance was 0.16 (0.10; 0.25) and the corresponding number for the coefficient of correlation between genes affecting mean and variance was −0.74 (−0.90;−0.52). It is argued that stronger support for the HET model than that derived from statistical analysis of data would be provided by a successful selection experiment designed to modify the environmental variance. A simple selection criterion is suggested (average squared deviation from the mean of repeated records within individuals) and its predicted response and variance under the HET model are derived. This is used to determine the appropriate size and length of a selection experiment designed to change the environmental variance. Results from the analytical expressions are compared with those obtained using simulation. There is good agreement provided selection intensity is not intense.
A Simple Formula for Obtaining Markedly Improved Mutation Rate Estimates
Authors: Gerrish Philip
Published: October 2008

In previous work by M. E. Jones and colleagues, it was shown that mutation rate estimates can be improved and corresponding confidence intervals tightened by following a very easy modification of the standard fluctuation assay: cultures are grown to a larger-than-usual final density, and mutants are screened for in only a fraction of the culture. Surprisingly, this very promising development has received limited attention, perhaps because there has been no efficient way to generate the predicted mutant distribution to obtain non-moment-based estimates of the mutation rate. Here, the improved fluctuation assay discovered by Jones and colleagues is made amenable to quantile-based, likelihood, and other Bayesian methods by a simple recursion formula that efficiently generates the entire mutant distribution after growth and dilution. This formula makes possible a further protocol improvement: grow cultures as large as is experimentally possible and severely dilute before plating to obtain easily countable numbers of mutants. A preliminary look at likelihood surfaces suggests that this easy protocol adjustment gives markedly improved mutation rate estimates and confidence intervals.
Unstable RNAi Effects Through Epigenetic Silencing of an Inverted Repeat Transgene in Chlamydomonas reinhardtii
Authors: Yamasaki Tomohito , Miyasaka Hitoshi , Ohama Takeshi
Published: October 2008

RNA interferences in the unicellular green alga, Chlamydomonas reinhardtii, can be silenced. We have used the silencing of a transgene (aadA) that confers resistance to spectinomycin to investigate the mechanisms responsible for silencing by an artificial inverted repeat (IR) of the aadA gene. The IR construct provided strong silencing, but the RNAi efficiency varied among subclones of a single RNAi-transformed strain with successive cell divisions. Northern blot analyses revealed an inverse correlation between the copy number of the hairpin RNA and the spectinomycin resistance of the subclones. There is an inverse correlation between the efficiency of RNAi and the frequency of methylated CpG (*CpG) in the silenced region. No significant methylated cytosine was observed in the target aadA gene, which suggests the absence of RNA-directed DNA methylation in trans. Several experiments suggest the existence of an intrinsic IR sequence-dependent but a transcription-independent DNA methylation system in C. reinhardtii. The correlation between the *CpG levels and the IR transcript implies the existence of IR DNA-dependent DNA methylation. Treatment of RNAi-induced cells with a histone deacetylase inhibitor, Trichostatin A, rapidly increased the amount of the hairpin RNA and suggests that transcription of the silencer construct was repressed by *CpG-related silencing mechanisms.
Recruitment of Saccharomyces cerevisiae Dnl4–Lif1 Complex to a Double-Strand Break Requires Interactions With Yku80 and the Xrs2 FHA Domain
Authors: Palmbos Phillip L , Wu Dongliang , Daley James M , Wilson Thomas E
Published: October 2008

Nonhomologous end joining (NHEJ) in yeast depends on eight different proteins in at least three different functional complexes: Yku70–Yku80 (Ku), Dnl4–Lif1–Nej1 (DNA ligase IV), and Mre11–Rad50–Xrs2 (MRX). Interactions between these complexes at DNA double-strand breaks (DSBs) are poorly understood but critical for the completion of repair. We previously identified two such contacts that are redundantly required for NHEJ, one between Dnl4 and the C terminus of Yku80 and one between the forkhead-associated (FHA) domain of Xrs2 and the C terminus of Lif1. Here, we first show that mutation of the Yku80 C terminus did not impair Ku binding to DSBs, supporting specificity of the mutant defect to the ligase interaction. We next show that the Xrs2–Lif1 interaction depends on Xrs2 FHA residues (R32, S47, R48, and K75) analogous to those known in other proteins to contact phosphorylated threonines. Two potential target threonines in Lif1 (T417 and T387) were inferred by identifying regions similar to a site in the human Lif1 homolog, XRCC4, known to be bound by the FHA domain of polynucleotide kinase. Mutating these threonines, especially T417, abolished the Xrs2–Lif1 interaction and impaired NHEJ epistatically with Xrs2 FHA mutation. Combining mutations that selectively disable the Yku80–Dnl4 and Xrs2–Lif1 interactions abrogated both NHEJ and DNA ligase IV recruitment to a DSB. The collected results indicate that the Xrs–Lif1 and Yku80–Dnl4 interactions are important for formation of a productive ligase–DSB intermediate.
Debating the Witch in the South African Context: Issues Arising from the Sapc Conference 2007
Authors: Wallace Dale Lancaster
Published: October 2008

No abstract required due to essay format
A Country for the Savant: Paganism, Popular Fiction and the Invention of Greece, 1914-1966
Authors: Freeman Nick
Published: October 2008

This essay explores the ways in which certain British writers reimagined Greece in the period 1914-66. It is especially concerned with the ways in which Greece represents a ‘pagan’ space in which characters encounter modes of living and belief far removed from those they are used to. With particular reference to John Buchan, Sarban, and Robert Aickman, the essay argues that the disparity between ‘real’ and ‘imagined’ Greece led writers into the deliberate fictionalisation of Mediterranean islands in search of a ‘paganism’ that may or may not actually exist.
A Self-Renewal Program Controls the Expansion of Genetically Unstable Cancer Stem Cells in Pluripotent Stem Cell-Derived Tumors
Authors: Conway Anne E. , Lindgren Anne , Galic Zoran , Pyle April D. , Wu Hong , Zack Jerome A. , Pelligrini Matteo , Teitell Michael A. , Clark Amander T.
Published: October 2008

Human germ cell tumors are often metastatic, presumably due to distal site tumor growth by cancer stem cells. To determine whether cancer stem cells can be identified in a transplantation model of testicular germ cell tumor, we transplanted murine embryonic germ cells (EGCs) into the testis of adult severe combined immunodeficient mice. Transplantation resulted in a locally invasive solid tumor, with a cellular component that generated secondary tumors upon serial transplantation. The secondary tumors were invariably metastatic, a feature not observed in the primary tumors derived from EGCs. To characterize the differences between EGCs and the tumor-derived stem cells, we performed karyotype and microarray analysis. Our results show that generation of cancer stem cells is associated with the acquisition of nonclonal genomic rearrangements not found in the originating population. Furthermore, pretreatment of EGCs with a potent inhibitor of self-renewal, retinoic acid, prevented tumor formation and the emergence of these genetically unstable cancer stem cells. Microarray analysis revealed that EGCs and first- and second-generation cancer stem cells were highly similar; however, approximately 1,000 differentially expressed transcripts could be identified corresponding to alterations in oncogenes and genes associated with motility and development. Combined, the data suggest that the activation of oncogenic pathways in a cellular background of genetic instability, coupled with an inherent ability to self-renew, is involved in the acquisition of metastatic behavior in the cancer stem cell population of tumors derived from pluripotent cells.
The Role of Lmx1a in the Differentiation of Human Embryonic Stem Cells into Midbrain Dopamine Neurons in Culture and After Transplantation into a Parkinson's Disease Model
Authors: Cai Jingli , Donaldson Angela , Yang Ming , German Michael S. , Enikolopov Grigori , Iacovitti Lorraine
Published: October 2008

Recent studies have provided important insight into the homeoprotein LIM homeobox transcription factor 1α (Lmx1a) and its role in the commitment of cells to a midbrain dopamine (mDA) fate in the developing mouse. We show here that Lmx1a also plays a pivotal role in the mDA differentiation of human embryonic stem (hES) cells. Thus, as indicated by small interfering RNA experiments, the transient early expression of Lmx1a is necessary for the coordinated expression of all other dopamine (DA)-specific phenotypic traits as hES cells move from multipotent human neural progenitor cells (hNPs) to more restricted precursor cells in vitro. Moreover, only Lmx1a-specified hNPs have the potential to differentiate into bona fide mDA neurons after transplantation into the 6-hydroxydopamine-treated rat striatum. In contrast, cortical human neuronal precursor cells (HNPCs) and mouse subventricular zone cells do not express Lmx1a or become mDA neurons even when placed in an environment that fosters their DA differentiation in vitro or in vivo. These findings suggest that Lmx1a may be critical to the development of mDA neurons from hES cells and that, along with other key early DA markers (i.e., Aldh1a1), may prove to be extremely useful for the selection of appropriately staged and suitably mDA-specified hES cells for cell replacement in Parkinson's disease.
Inspection and maintenance of highway structures in England
Authors: Jandu A. S.
Published: October 2008

This paper describes the inspection and maintenance of highway structures by the Highways Agency in England. It provides a background to the inspection requirements, the assets managed and maintenance activities. The network is divided into 14 areas. The inspection and maintenance activities are undertaken by managing agents and contractors appointed by the Highways Agency for a period of 5 to 7 years. There are also sections of the network that are under the control of the design, build, finance and operate organisations. The inspection and maintenance processes are managed through a structures management and information system (SMIS), which is available to all managing agents. A risk-based value management process is used for the selection of suitable maintenance projects to be undertaken. The Highways Agency has in place robust processes for the inspection and maintenance of highways structures to ensure structural and public safety.