bluuebunny/crossref_metadata_2025 huggingface dataset:
The said and the unsaid: Performative guiding in a Jerusalem neighbourhood
Authors: Brin Eldad , Noy Chaim
Published: December 2010

This paper describes a guided walking tour of a formerly Palestinian neighbourhood in Jerusalem and an important battlefield in the 1948 Arab—Israeli War.The paper assumes a critical performance approach to guided tours in examining how through performative guiding, identities, histories and places are (re)constituted. We conceive of performative guiding as a situated event which both takes place in and simultaneously signifies and reconstructs the environment wherein it transpires. The tour we analyse was given by a Jewish-Israeli guide to a Jewish-Israeli audience, and was attended by the first author. The guide’s apparent inclination towards the Israeli and Zionist narrative regarding the story of the neighbourhood is highlighted through an analysis of the commentary given. Through an examination of things said and unsaid, we highlight the dual role of performative guiding: relaying historical information and reaffirming partisan narratives.
(re)Imaging Māori tourism: Representation and cultural hybridity in postcolonial New Zealand
Authors: Amoamo Maria , Thompson Anna
Published: December 2010

This paper is concerned with issues of cultural representation and postcolonialism. It argues that in countries with a history of colonization ‘indigenous culture’ has often been (mis)represented in the media associated with tourism promotion. The impact of such marketing is reflected in the call by indigenous tourism stakeholders to control the representation and meanings of their image, tribal identities and cultural difference. This study seeks to advance academic discussion on Bhabha’s concept of hybridity as a means to understand the transformative and dynamic interplay of cultural change and cultural production within a tourism context. A qualitative approach using in-depth case studies of Māori tourism businesses and stakeholders in New Zealand reveals the hybridized nature of Māori identity.This contests established categorizations of culture and identity through creative ‘ third spaces’ that re-inscribe notions of the Other. In turn, hybridity promotes counter-representations that present new strategies of self-determination and resistance for indigenous peoples.
‘The man from New Line knocked on the door’: Tourism, media power, and Hobbiton/Matamata as boundaried space
Authors: Moses Peaslee Robert
Published: December 2010

This study investigates the emergence and maintenance of tourist activity surrounding the film location site of ‘Hobbiton’, constructed during the filming of the Lord of the Rings film trilogy.The paper engages the theoretical propositions of Nick Couldry, who detects the presence of media power in those places that are boundaried as ‘special’ in terms of their mediation and that motivate certain reificational behaviors and attitudes in their visitors. Moreover, the paper considers Michel de Certeau’s location of the subversion of power structures in what he calls the ‘enunciation’ of discursive material. Reporting on ethnographic fieldwork, including participant observation of the tour experience and interviews with Hobbiton tourism providers, local community members, and the owners of the property in question, the study concludes that the activity surrounding Hobbiton is emblematic of an embodied assent to the kind of normative media categories named in Couldry’s work.
Foreign expatriate service provision in Portugal’s Algarve
Authors: Eaton Martin
Published: December 2010

Portugal’s Algarve is home to a fusion of tourism activities, indigenous populations, inflowing holidaymakers and migrant settlers. This article investigates business development processes amongst 43 foreign expatriate service providers (FESPs) in Alvor and Albufeira. Many of these immigrant entrepreneurs believe that their businesses are functioning satisfactorily, are well established and are providing a range of traditional and niche service activities. Feminization of ownership is important, with several taking advantage of supportive co-preneurial relationships.This enterprising picture is linked to the ontological condition and use of a neutral language economy when discussing customer behaviour. Other key determinants include insular business practices and limited interplay with tourism authorities. Despite recession and competitive strains, it is argued that FESPs are playing significant roles, fostering social integration, providing jobs, and contributing to the resilient socio-economic performance found at these localized scales of analysis.
‘A new view of body image’: A school-based participatory action research project with young Aboriginal women
Authors: McHugh Tara-Leigh F , Kowalski Kent C
Published: December 2010

The body image experiences of young Aboriginal women are very complex and influence health in a variety of ways; subsequently, young Aboriginal women have voiced the need for action. The purpose of our research was to engage in a collaborative, school-based participatory action research (PAR) project in partnership with a local high school to provide young women, primarily young Aboriginal women, with an opportunity to manage their body image experiences in an effective manner. Students, teachers, and staff of Nutana Collegiate in Saskatchewan, Canada participated in this project, which took place from September 2006 to June 2007. The two primary phases of this PAR project were focused on building relationships and collaboratively developing action initiatives. The development and implementation of action at the individual, school, provincial, and national levels was the most significant outcome of this research. Findings suggest that universities and local high schools can and should work together to develop school-based body image programs for young Aboriginal women. As well, and maybe most importantly, this research highlights the strength of using PAR methodologies when engaging young Aboriginal women in body image research.
Towards greater consistency in sentencing: Findings from a survey of Belgian magistrates
Authors: Monsieurs Annemie , Vanderhallen Miet , Rozie Joëlle
Published: December 2010

The need for more consistency in sentencing is becoming an increasingly prominent issue in judicial debates in Belgium. The present study examines the desirability and the possibility of enhancing consistency in sentencing in Belgium. As in many other countries, Belgian magistrates possess very wide discretion in sentencing. Like most other continental magistrates, however, Belgian magistrates have no sentencing guidelines or other helpful documents at their disposal. In order to gain insight into the possibility of implementing sentencing guidelines, the opinion of magistrates regarding increased consistency in sentencing was explored. Do magistrates perceive that there are inconsistencies in sentencing? What do they think about consistency in sentencing? These and other questions were asked in a survey distributed among Flemish magistrates. The findings of this exploratory study reveal that Flemish magistrates have a positive attitude towards consistency in sentencing.
Increasing the Proportion of Autologous Arteriovenous Fistulas Does Not Diminish Fistula Patency
Authors: Ruddy Jean Marie , Brothers Thomas E. , Robison Jacob G. , Elliott Bruce M.
Published: December 2010

Objective: Arteriovenous fistulas (AVF) constructed before and after initiating the kidney disease outcomes and quality initiative (KDOQI) guidelines were reviewed at a single academic center to identify decreased patency with use of potentially inferior vein conduits. Methods: Primary access procedures performed pre- and post-adoption of KDOQI guidelines were compared for the primary outcomes of maturation rate and primary patency and the secondary outcome of access utilization. Results: The proportion of autologous AVFs created was higher post-KDOQI (73% vs 35%, P < .001), and an increased use of the basilic vein was observed (20% vs 2%, P < .05). The failure rate of fistula maturation was reduced post-KDOQI (24% vs 38%, P < .05); however, access utilization was also decreased (59% vs 75%, P < .001). Conclusions: Adherence to KDOQI guidelines for AVFs does not compromise fistula patency and increased use of the basilic vein may lead to superior fistula maturation rates. Early referral may result in lower fistula utilization rates, however.
Student Perceptions of Sexual Assault Resources and Prevalence of Rape Myth Attitudes
Authors: Hayes-Smith Rebecca M. , Levett Lora M.
Published: December 2010

This study investigated whether students at a large, public university were receiving sexual assault resource information, whether the information was informative, and whether it was successful in dispelling commonly held rape myths. Findings suggest that students may not be receiving sexual assault information even though it was available on campus. If students reported receiving sexual assault information, they did not report much knowledge about its contents. In addition, knowledge of resources was not indicative of a lowered belief in rape myths. However, female students were less likely to believe in rape myths compared to male students. Students recommended innovative ways the university could disseminate information and these suggestions are discussed.
“The Chain Has to Be Broken”: A Qualitative Investigation of the Experiences of Young Women Following Juvenile Court Involvement
Authors: Bright Charlotte Lyn , Ward Sara K. , Junko Negi Nalini
Published: December 2010

Whereas the number of girls involved in the juvenile justice system is on the rise, little is known about female juvenile offenders after they reach adulthood. This study aims to explore the meaning that young adult women ascribe to their juvenile court experiences and assess their perceptions of facilitators and barriers to progress in their adult lives. Data on services and support are presented from nine semistructured interviews. Findings include the commonality of mental health issues, substance abuse, and problematic relationships with intimate partners. Implications for service provision and policy, as well as future research directions, are outlined.
Optimal Normative Pediatric Cardiac Structure Dimensions for Clinical Use
Authors: Awori Mark N. , Finucane Kirsten , Gentles Thomas L.
Published: December 2010

Cardiac structure size influences surgical decision making in pediatric cardiac surgery. Lack of universally adopted normative cardiac structure dimensions may confound decision making. A review of the relevant literature contained in 2 large databases was performed with a view to determine the optimal normative cardiac structure dimensions for clinical use. The current article initially discusses technical issues related to cardiac structure measurement and measurement normalization. It then describes the literature search strategy and examines the quality of published data in subjects below 19 years of age. The optimal normative dimension data set is then recommended.
Congenitally Corrected Transposition of Great Arteries
Authors: Said Sameh M. , Burkhart Harold M. , Schaff Hartzell V. , Dearani Joseph A.
Published: December 2010

In patients with congenitally corrected transposition of the great arteries, the main concern has been the long-term performance of the morphologic right ventricle in association with tricuspid valve regurgitation when it remains as the systemic ventricle. Deterioration in ventricular function can occur slowly over many years, even without associated cardiac anomalies or previous surgical interventions. This review summarizes the authors' experience and provides a thorough review of the literature addressing the management of the failing systemic right ventricle as well as the tricuspid valve regurgitation with congenitally corrected transposition. This includes different surgical options, the authors' preferred management algorithm, and the late outcome.
Critical Pulmonary Stenosis
Authors: Kumar Bhupesh , Puri G. D. , Singh Anju , Rana S. S.
Published: December 2010

A 20-day-old girl was diagnosed with critical pulmonary valvular stenosis with patent ductus arteriosus (PDA). She underwent surgical pulmonary valvotomy and infundibular resection. A trial snaring of the PDA resulted in significant systemic desaturation, and the PDA was left undivided. A continuous infusion of prostaglandin was used to keep the PDA open for the next 8 days. The PDA acted as a “natural systemic-to-pulmonary shunt” to provide pulmonary blood flow until right ventricular compliance and function improved. The various causes of persistent desaturation following pulmonary valvotomy are discussed.
Echocardiography for Discordant Atrioventricular Connections
Authors: Marx Gerald Ross
Published: December 2010

An understanding of the nomenclature of discordant atrioventricular connections is necessary to understand the corresponding anatomy and hence physiology of this rare, and complex heart defect. Echocardiography is an important imaging modality for the diagnosis of discordant atrioventricular connections. The morphology of the atria, ventricles and great arteries can be determined by echocardiography. A precise and organized segmental approach to the echocardiographic examination can establish the diagnosis and associated abnormalities. Such an approach is essential for the initial diagnosis, to help guide medical and surgical intervention, and evaluate the corresponding response to intervention in these patients.
Pulmonary Arteriovenous Malformations in Heterotaxy Syndrome
Authors: Burstein Danielle S. , Mavroudis Constantine , Puchalski Michael D. , Stewart Robert D. , Blanco Carlos J. , Jacobs Marshall L.
Published: December 2010

We report a surgical approach using hepatic vein–to–azygos vein connection without cardiopulmonary bypass or deep hypothermic circulatory arrest in a patient with heterotaxy syndrome and interrupted inferior vena cava with persistence of pulmonary arteriovenous malformations (PAVMs) after previous Fontan completion. We advocate early performance of hepatic vein–to–azygos vein connection following the Kawashima operation for heterotaxy with functionally univentricular heart and interrupted inferior vena cava. We review the physiology of heterotaxy syndrome with congenital heart disease and justify our approach in the context of a review of previous surgical strategies used in this patient population.
The Natural History of Congenitally Corrected Transposition of the Great Arteries
Authors: Huhta James
Published: December 2010

The natural history of congenitally corrected transposition of the great arteries is of clinical/surgical importance once the fetus is born without heart block or signs of heart failure. Without significant tricuspid valve malformation, associated defects such as ventricular septal defect and left ventricular outflow obstruction can be repaired surgically. The mortality and long-term outcome appear to be linked strongly with the severity of tricuspid valve regurgitation. Some patients with an intact ventricular septum and no right ventricular dysfunction will live long lives without detection, and some women will successfully complete pregnancy.
Microemboli Detection and Classification During Pediatric Cardiopulmonary Bypass
Authors: Clark Joseph B. , Qiu Feng , Guan Yulong , Woitas Karl R. , Myers John L. , Undar Akif
Published: December 2010

Microemboli may be a cause of postoperative neurological morbidity. Improved detection of microemboli may lead to better strategies to minimize embolization and improve neurological outcomes. Transcranial Doppler may have limited sensitivity for very small microemboli. The Emboli Detection and Classification (EDAC) Quantifier offers increased sensitivity (10 μm) and potentially improved capability for microemboli monitoring. EDAC was used to measure microemboli in the cardiopulmonary bypass circuit during 33 pediatric heart operations. More microemboli were detected in the venous than the arterial line (median, 11,830 vs 1298). Venous microemboli tended to be larger in size than arterial microemboli (>40 μm; 59% vs 7%). Increased venous and arterial microemboli were seen at the onset of bypass; increased venous microemboli were also seen with clamp removal. Thousands of microemboli <40 μm are transmitted to pediatric patients during heart surgery. Initiation of bypass may be a key offender and may result from air in the venous line. Although the significance of microemboli remains unknown, increased awareness may lead to improved techniques to minimize microemboli, with improvement in neurological outcomes.
Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression
Authors: Iriuchishima Hirono , Takubo Keiyo , Matsuoka Sahoko , Onoyama Ichiro , Nakayama Keiichi I. , Nojima Yoshihisa , Suda Toshio
Published: December 2010

Cell-cycle quiescence in hematopoietic stem cells (HSCs) is essential for maintaining stemness by protecting cells from differentiation or senescence. F-box and WD-40 domain protein 7 (Fbxw7) maintains HSCs and suppresses leukemogenesis by mediating ubiquitin-dependent degradation of cell-cycle activators and oncoproteins. Fbxw7α was shown to be the preferentially expressed Fbxw7 isoform in primitive HSCs. Forced Fbxw7α expression in lineage marker Sca-1+c-Kit+ cells led to cell-cycle dormancy by reducing the protein levels of the Fbxw7 substrates c-Myc, Notch1, and phosphorylated S6 (a key downstream element of mTOR). Hypoxia, an essential factor for HSC quiescence, suppressed c-Myc in an Fbxw7α-dependent manner. Fbxw7α-overexpressing lineage marker Sca-1+c-Kit+ cells sustained high reconstitution capacities during in vitro culture. These data suggest that Fbxw7α sustains HSC dormancy through c-Myc, Notch1, and the mTOR pathways. The modulation of Fbxw7α expression or activity represents a promising new tool for ex vivo HSC maintenance.
Rara haploinsufficiency modestly influences the phenotype of acute promyelocytic leukemia in mice
Authors: Welch John S. , Klco Jeffery M. , Varghese Nobish , Nagarajan Rakesh , Ley Timothy J.
Published: December 2010

RARA (retinoic acid receptor alpha) haploinsufficiency is an invariable consequence of t(15;17)(q22;q21) translocations in acute promyelocytic leukemia (APL). Retinoids and RARA activity have been implicated in hematopoietic self-renewal and neutrophil maturation. We and others therefore predicted that RARA haploinsufficiency would contribute to APL pathogenesis. To test this hypothesis, we crossed Rara+/− mice with mice expressing PML (promyelocytic leukemia)-RARA from the cathepsin G locus (mCG-PR). We found that Rara haploinsufficiency cooperated with PML-RARA, but only modestly influenced the preleukemic and leukemic phenotype. Bone marrow from mCG-PR+/− × Rara+/− mice had decreased numbers of mature myeloid cells, increased ex vivo myeloid cell proliferation, and increased competitive advantage after transplantation. Rara haploinsufficiency did not alter mCG-PR–dependent leukemic latency or penetrance, but did influence the distribution of leukemic cells; leukemia in mCG-PR+/− × Rara+/− mice presented more commonly with low to normal white blood cell counts and with myeloid infiltration of lymph nodes. APL cells from these mice were responsive to all-trans retinoic acid and had virtually no differences in expression profiling compared with tumors arising in mCG-PR+/− × Rara+/+ mice. These data show that Rara haploinsufficiency (like Pml haploinsufficiency and RARA-PML) can cooperate with PML-RARA to influence the pathogenesis of APL in mice, but that PML-RARA is the t(15;17) disease-initiating mutation.
An observational study of outcomes after initial infused therapy in Medicare patients diagnosed with chronic lymphocytic leukemia
Authors: Danese Mark D. , Griffiths Robert I. , Gleeson Michelle , Satram-Hoang Sacha , Knopf Kevin , Mikhael Joseph , Reyes Carolina
Published: December 2010

The study goal was to characterize older chronic lymphocytic leukemia (CLL) patients and to evaluate outcomes in those patients who initiated infused therapy. Patients 66 years of age and older in the Surveillance, Epidemiology, and End Results (SEER) program with a CLL diagnosis were matched to their Medicare Part A and Part B claims for long-term follow-up. Treatment patterns, survival after initiation of infused therapy, and both hematologic and hospitalization outcomes were assessed. There were 6433 CLL patients identified, and 2040 received infused therapy. Treated patients were categorized as receiving rituximab monotherapy (16%), rituximab plus chemotherapy (14%), and chemotherapy alone (70%) based on the initial 60 days after infusion. Rituximab plus chemotherapy compared with chemotherapy alone was associated with a 25% lower risk of overall mortality (95% confidence interval, 9%-38%). Restricting to patients age 70 years and older did not change the risk reduction for rituximab plus chemotherapy. Hematologic interventions were more common with rituximab plus chemotherapy compared with chemotherapy alone, but there was no difference in all-cause hospitalizations. These analyses, based on observational data, suggest that the benefits of initial therapy with rituximab in a heterogeneous group of older CLL patients are comparable with those demonstrated in younger patients.
Effects of a partly self-administered exercise program before, during, and after allogeneic stem cell transplantation
Authors: Wiskemann Joachim , Dreger Peter , Schwerdtfeger Rainer , Bondong Andrea , Huber Gerhard , Kleindienst Nikolaus , Ulrich Cornelia M. , Bohus Martin
Published: December 2010

Before, during, and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), patients experience considerable physical and psychologic distress. Besides graft-versus-host disease and infections, reduced physical performance and high levels of fatigue affect patients' quality of life. This multicenter randomized controlled trial examined the effects of a partly self-administered exercise intervention before, during, and after allo-HSCT on these side effects. After randomization to an exercise and a social contact control group 105 patients trained in a home-based setting before hospital admission, during inpatient treatment and a 6- to 8-week period after discharge. Fatigue, physical performance, quality of life, and physical/psychologic distress were measured by standardized instruments at baseline, admission to, and discharge from hospital and 6 to 8 weeks after discharge. The exercise group showed significantly improvement in fatigue scores (up to 15% improvement in exercise group vs up to 28% deterioration in control; P < .01-.03), physical fitness/functioning (P = .02-.03) and global distress (P = .03). All effects were at least detectable at one assessment time point after hospitalization or repeatedly. Physical fitness correlated significantly with all reported symptoms/variables. In conclusion, this partly supervised exercise intervention is beneficial for patients undergoing allo-HSCT. Because of low personnel requirements, it might be valuable to integrate such a program into standard medical care.
Induction of Ca2+-driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2–IP3 receptor interaction
Authors: Zhong Fei , Harr Michael W. , Bultynck Geert , Monaco Giovanni , Parys Jan B. , De Smedt Humbert , Rong Yi-Ping , Molitoris Jason K. , Lam Minh , Ryder Christopher , Matsuyama Shigemi , Distelhorst Clark W.
Published: December 2010

Bcl-2 contributes to the pathophysiology and therapeutic resistance of chronic lymphocytic leukemia (CLL). Therefore, developing inhibitors of this protein based on a thorough understanding of its mechanism of action is an active and promising area of inquiry. One approach centers on agents (eg, ABT-737) that compete with proapoptotic members of the Bcl-2 protein family for binding in the hydrophobic groove formed by the BH1-BH3 domains of Bcl-2. Another region of Bcl-2, the BH4 domain, also contributes to the antiapoptotic activity of Bcl-2 by binding to the inositol 1,4,5-trisphosphate receptor (IP3R) Ca2+ channel, inhibiting IP3-dependent Ca2+ release from the endoplasmic reticulum. We report that a novel synthetic peptide, modeled after the Bcl-2–interacting site on the IP3R, binds to the BH4 domain of Bcl-2 and functions as a competitive inhibitor of the Bcl-2–IP3R interaction. By disrupting the Bcl-2–IP3R interaction, this peptide induces an IP3R-dependent Ca2+ elevation in lymphoma and leukemia cell lines and in primary CLL cells. The Ca2+ elevation evoked by this peptide induces apoptosis in CLL cells, but not in normal peripheral blood lymphocytes, suggesting the involvement of the Bcl-2–IP3R interaction in the molecular mechanism of CLL and indicating the potential merit of targeting this interaction therapeutically.
Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation
Authors: Yap Damian B. , Chu Justin , Berg Tobias , Schapira Matthieu , Cheng S.-W. Grace , Moradian Annie , Morin Ryan D. , Mungall Andrew J. , Meissner Barbara , Boyle Merrill , Marquez Victor E. , Marra Marco A. , Gascoyne Randy D. , Humphries R. Keith , Arrowsmith Cheryl H. , Morin Gregg B. , Aparicio Samuel A. J. R.
Published: December 2010

Next-generation sequencing of follicular lymphoma and diffuse-large B-cell lymphoma has revealed frequent somatic, heterozygous Y641 mutations in the histone methyltransferase EZH2. Heterozygosity and the presence of equal quantities of both mutant and wild-type mRNA and expressed protein suggest a dominant mode of action. Surprisingly, B-cell lymphoma cell lines and lymphoma samples harboring heterozygous EZH2Y641 mutations have increased levels of histone H3 Lys-27–specific trimethylation (H3K27me3). Expression of EZH2Y641F/N mutants in cells with EZH2WT resulted in an increase of H3K27me3 levels in vivo. Structural modeling of EZH2Y641 mutants suggests a “Tyr/Phe switch” model whereby structurally neutral, nontyrosine residues at position 641 would decrease affinity for unmethylated and monomethylated H3K27 substrates and potentially favor trimethylation. We demonstrate, using in vitro enzyme assays of reconstituted PRC2 complexes, that Y641 mutations result in a decrease in monomethylation and an increase in trimethylation activity of the enzyme relative to the wild-type enzyme. This represents the first example of a disease-associated gain-of-function mutation in a histone methyltransferase, whereby somatic EZH2 Y641 mutations in lymphoma act dominantly to increase, rather than decrease, histone methylation. The dominant mode of action suggests that allele-specific EZH2 inhibitors should be a future therapeutic strategy for this disease.
Loss of Canonical Insulin Signaling Accelerates Vascular Smooth Muscle Cell Proliferation and Migration Through Changes in p27Kip1 Regulation
Authors: Lightell Daniel James , Moss Stephanie Collier , Woods Thomas Cooper
Published: December 2010

Insulin resistance is associated with an accelerated rate of atherosclerosis. Vascular smooth muscle cell (VSMC) migration and proliferation are important components of atherosclerosis. To elucidate the effects of the loss of normal insulin receptor (IR) signaling on VSMC function, we compared the proliferation and migration of murine VSMCs lacking the IR (L2-VSMCs) with wild type (WT-VSMCs). We also examined changes in the response of L2-VSMCs to insulin stimulation and to inhibition of the mammalian target of rapamycin (mTOR), a kinase critical in VSMC proliferation and migration. The L2-VSMCs exhibit greater proliferation and migration rates compared with WT-VSMCs. L2-VSMCs also exhibit a resistance to the effects of rapamycin, an mTOR inhibitor, on proliferation, migration, and cell cycle progression. The resistance to mTOR inhibition is coupled with a loss of effect on the cyclin-dependent kinase inhibitor p27Kip1, an inhibitor of cell cycle progression and VSMC migration. In response to stimulation with physiological insulin, the L2-VSMCs exhibit a loss of Akt phosphorylation and a significantly increased activation of the ERK-1/2 compared with WT-VSMCs. Insulin stimulation also decreased p27Kip1 mRNA in L2-VSMCs but not in WT-VSMCs. The effect of insulin on p27Kip1 mRNA was blocked by pretreatment with an ERK-1/2 pathway inhibitor. We conclude that loss of canonical insulin signaling results in increased ERK-1/2 activation in response to physiological insulin that decreases p27Kip1 mRNA. These data demonstrate a potential mechanism where changes in IR signaling could lead to a decrease in p27Kip1, accelerating VSMC proliferation and migration.
The Transcription Factor B-Cell Lymphoma (BCL)-6 Modulates Pancreatic β-Cell Inflammatory Responses
Authors: Igoillo-Esteve Mariana , Gurzov Esteban N. , Eizirik Décio L. , Cnop Miriam
Published: December 2010

Type 1 diabetes is a chronic autoimmune disease with a strong inflammatory component. We have previously shown that expression of the transcriptional repressor B-cell lymphoma (BCL)-6 is very low in pancreatic β-cells, which may favor prolonged proinflammatory responses after exposure to the cytokines IL-1β and interferon γ. Here we investigated whether cytokine-induced inflammation and apoptosis can be prevented in β-cells by BCL-6 expression using plasmid, prolactin, and adenoviral approaches. The induction of mild or abundant BCL-6 expression in β-cells by prolactin or an adenoviral BCL-6 expression construct, respectively, reduced cytokine-induced inflammatory responses in a dose-dependent manner through inhibition of nuclear factor-κB activation. BCL-6 decreased Fas and inducible nitric oxide synthase expression and nitric oxide production, but it inhibited the expression of the antiapoptotic proteins Bcl-2 and JunB while increasing the expression of the proapoptotic death protein 5. The net result of these opposite effects was an augmentation of β-cell apoptosis. In conclusion, BCL-6 expression tones down the unrestrained cytokine-induced proinflammatory response of β-cells but it also favors gene networks leading to apoptosis. This suggests that cytokine-induced proinflammatory and proapoptotic signals can be dissociated in β-cells. Further understanding of these pathways may open new possibilities to improve β-cell survival in early type 1 diabetes or after transplantation.
Hnrnpk, a Protein Differentially Expressed in Immature Rat Ovarian Development, Is Required for Normal Primordial Follicle Assembly and Development
Authors: Wang Ningling , Zhang Ping , Guo Xuejiang , Zhou Zuomin , Sha Jiahao
Published: December 2010

The formation of ovarian follicles and subsequent development after birth are critical processes for female reproduction, and inappropriate coordination of these processes contributes to ovarian pathologies, such as premature ovarian failure and infertility. Identification and functional investigation of the factors involved in follicular assembly and the initial recruitment will be of great significance to the understanding of the female reproduction process. In this study, we examined the roles of transcription factor heterogeneous nuclear ribonucleoprotein K (Hnrnpk) in rat primordial folliculogenesis using RNA interference knockdown strategies. Reducing Hnrnpk mRNA levels via Hnrnpk small interfering RNAs to neonatal ovaries resulted in a substantial loss of naked oocytes, primordial and primary follicles. Structure disorganization of the ovary characterized by groups of oocytes arranged in nests, clusters of somatic cells not associated with any oocytes and many highly condensed oocyte nuclei was observed. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay demonstrated that these abnormalities may be partially attributable to abnormal apoptosis of oocytes. Furthermore, the microarray analysis showed that 63 genes changed significantly (≥2-folds or ≤0.5-fold) between the ovaries treated with Hnrnpk small interfering RNAs and the controls, with 22 up-regulated genes and 41 down-regulated genes. These differentially expressed genes were involved in several critical biological processes in ovarian development. These results suggest that transcription factor Hnrnpk is a key regulator for primordial follicle assembly and development, which provides a new potential therapeutic target to regulate ovarian function and treat ovarian disease.
Endocrine Disruption of Brain Sexual Differentiation by Developmental PCB Exposure
Authors: Dickerson Sarah M. , Cunningham Stephanie L. , Patisaul Heather B. , Woller Michael J. , Gore Andrea C.
Published: December 2010

In mammals, sexual differentiation of the hypothalamus occurs during prenatal and early postnatal development due in large part to sex differences in hormones. These early organizational processes are critically important for the attainment and maintenance of adult reproductive functions. We tested the hypothesis that perinatal exposure to polychlorinated biphenyls (PCBs) that disrupt hormonal pathways would perturb reproductive maturation and the sexually dimorphic development of neuroendocrine systems in the preoptic area (POA). Pregnant Sprague-Dawley rats were injected on gestational d 16 and 18 with vehicle (dimethylsulfoxide), Aroclor 1221 (A1221, an estrogenic PCB mix), a reconstituted PCB mixture representing those highest in human body burden (PCBs 138, 153, 180), or estradiol benzoate, an estrogenic control. Male and female pups were monitored for somatic and reproductive development. In adulthood, some rats were perfused and used for immunohistochemistry of estrogen receptor α, kisspeptin, and coexpression of Fos in GnRH neurons. Other rats were used to obtain fresh-frozen POA dissections for use in a PCR-based 48-gene expression array. Pubertal onset was advanced and estrous cyclicity irregular in endocrine-disrupted females. Furthermore, sexual differentiation of female neuroendocrine systems was masculinized/defeminized. Specifically, in the adult female anteroventral periventricular nucleus, estrogen receptor α-cell numbers and kisspeptin fiber density were significantly decreased, as was GnRH-Fos coexpression. PCR analysis identified androgen receptor, IGF-I, N-methyl-d-aspartate receptor subunit NR2b, and TGFβ1 mRNAs as significantly down-regulated in endocrine-disrupted female POAs. These data suggest that developmental PCBs profoundly impair the sexual differentiation of the female hypothalamus.
Modeling Human Endometrial Decidualization from the Interaction between Proteome and Secretome
Authors: Garrido-Gomez Tamara , Dominguez Francisco , Lopez Juan Antonio , Camafeita Emilio , Quiñonero Alicia , Martinez-Conejero Jose Antonio , Pellicer Antonio , Conesa Ana , Simón Carlos
Published: December 2010

Context:

Decidualization of the human endometrium, which involves morphological and biochemical modifications of the endometrial stromal cells (ESCs), is a prerequisite for adequate trophoblast invasion and placenta formation.

Objective:

This study aims to investigate the proteome and secretome of in vitro decidualized ESCs. These data were combined with published genomic information and integrated to model the human decidualization interactome.

Design:

Prospective experimental case–control study.

Setting:

A private research foundation.

Patients:

Sixteen healthy volunteer ovum donors.

Intervention:

Endometrial samples were obtained, and ESCs were isolated and decidualized in vitro.

Main Outcome Measures:

Two-dimensional difference in-gel electrophoresis, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry, Western blot, human protein cytokine array, ELISA, and bioinformatics analysis were performed.

Results:

The proteomic analysis revealed 60 differentially expressed proteins (36 over- and 24 underexpressed) in decidualized versus control ESCs, including known decidualization markers (cathepsin B) and new biomarkers (transglutaminase 2, peroxiredoxin 4, and the ACTB protein). In the secretomic analysis, a total of 13 secreted proteins (11 up- and 2 down-regulated) were identified, including well-recognized markers (IGF binding protein-1 and prolactin) and novel ones (myeloid progenitor inhibitory factor-1 and platelet endothelial cell adhesion molecule-1). These proteome/secretome profiles have been integrated into a decidualization interactome model.

Conclusions:

Proteomic and secretomic have been used as hypothesis-free approaches together with complex bioinformatics to model the human decidual interactome for the first time. We confirm previous knowledge, describe new molecules, and we have built up a model for human in vitro decidualization as invaluable tool for the diagnosis, therapy, and interpretation of biological phenomena.
A High-Fat Diet Elicits Differential Responses in Genes Coordinating Oxidative Metabolism in Skeletal Muscle of Lean and Obese Individuals
Authors: Boyle K. E. , Canham J. P. , Consitt L. A. , Zheng D. , Koves T. R. , Gavin T. P. , Holbert D. , Neufer P. D. , Ilkayeva O. , Muoio D. M. , Houmard J. A.
Published: December 2010

Context:

In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised.

Objective:

To determine whether the responses of genes regulating lipid oxidation in skeletal muscle differed between lean and insulin resistant obese humans upon exposure to a high-fat diet (HFD).

Design and Setting:

A 5-d prospective study conducted in the research unit of an academic center.

Participants:

Healthy, lean (n = 12; body mass index = 22.1 ± 0.6 kg/m2), and obese (n=10; body mass index = 39.6 ± 1.7 kg/m2) males and females, between ages 18 and 30.

Intervention:

Participants were studied before and after a 5-d HFD (65% fat).

Main Outcome Measures:

Skeletal muscle biopsies (vastus lateralis) were obtained in the fasted and fed states before and after the HFD and mRNA content for genes involved with lipid oxidation determined. Skeletal muscle acylcarnitine content was determined in the fed states before and after the HFD.

Results:

Peroxisome proliferator activated receptor (PPAR) α mRNA content increased in lean, but not obese, subjects after a single high-fat meal. From Pre- to Post-HFD, mRNA content exhibited a body size × HFD interaction, where the lean individuals increased while the obese individuals decreased mRNA content for pyruvate dehydrogenase kinase 4, uncoupling protein 3, PPARα, and PPARγ coactivator-1α (P ≤ 0.05). In the obese subjects medium-chain acylcarnitine species tended to accumulate, whereas no change or a reduction was evident in the lean individuals.

Conclusions:

These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans.
The Knowledge-Gradient Algorithm for Sequencing Experiments in Drug Discovery
Authors: Negoescu Diana M. , Frazier Peter I. , Powell Warren B.
Published: December 2010

We present a new technique for adaptively choosing the sequence of molecular compounds to test in drug discovery. Beginning with a base compound, we consider the problem of searching for a chemical derivative of the molecule that best treats a given disease. The problem of choosing molecules to test to maximize the expected quality of the best compound discovered may be formulated mathematically as a ranking-and-selection problem in which each molecule is an alternative. We apply a recently developed algorithm, known as the knowledge-gradient algorithm, that uses correlations in our Bayesian prior distribution between the performance of different alternatives (molecules) to dramatically reduce the number of molecular tests required, but it has heavy computational requirements that limit the number of possible alternatives to a few thousand. We develop computational improvements that allow the knowledge-gradient method to consider much larger sets of alternatives, and we demonstrate the method on a problem with 87,120 alternatives.
Solving Large p-Median Problems with a Radius Formulation
Authors: García Sergio , Labbé Martine , Marín Alfredo
Published: December 2010

By means of a model based on a set covering formulation, it is shown how the p-median problem can be solved with just a column generation approach that is embedded in a branch-and-bound framework based on dynamic reliability branching. This method is more than competitive in terms of computational times and size of the instances that have been optimally solved. In particular, problems of a size larger than the largest ones considered in the literature up to now are solved exactly in this paper.
Combination of Nonlinear and Linear Optimization of Transient Gas Networks
Authors: Domschke Pia , Geißler Bjorn , Kolb Oliver , Lang Jens , Martin Alexander , Morsi Antonio
Published: December 2010

In this paper, we study the problem of technical transient gas network optimization, which can be considered a minimum cost flow problem with a nonlinear objective function and additional nonlinear constraints on the network arcs. Applying an implicit box scheme to the isothermal Euler equation, we derive a mixed-integer nonlinear program. This is solved by means of a combination of (i) a novel mixed-integer linear programming approach based on piecewise linearization and (ii) a classical sequential quadratic program applied for given combinatorial constraints. Numerical experiments show that better approximations to the optimal control problem can be obtained by using solutions of the sequential quadratic programming algorithm to improve the mixed-integer linear program. Moreover, iteratively applying these two techniques improves the results even further.
Efficient and Reliable Computation of Birth-Death Process Performance Measures
Authors: Ingolfsson Armann , Tang Ling
Published: December 2010

We present an efficient, reliable, and easy-to-implement algorithm to compute steady-state probabilities for birth-death processes whose upper-tail probabilities decay geometrically or faster. The algorithm can provide any required accuracy and avoids over- and underflow. In addition to steady-state probabilities, the algorithm can compute any performance measure that can be expressed as the expected value of a function of the population size, for nonnegative functions that are bounded by a constant, linear, or quadratic function of population size. The algorithm works with conditional steady-state probabilities, given that the population is in a range that is extended up and down as the algorithm progresses. These conditional probabilities facilitate the derivation of truncation error bounds. We illustrate the application of the algorithm to the Erlang B, C, and A queueing systems.
Channel Stuffing with Short-Term Interest in Market Value
Authors: Lai Guoming , Debo Laurens , Nan Lin
Published: December 2010

We study how a manager's short-term interest in the firm's market value may motivate channel stuffing: shipping excess inventory to the downstream channel. Channel stuffing allows a manager to report sales in excess of demand in order to influence investors' valuation of the firm. We apply an inventory model that highlights the potential role of inventory in the manager's channel stuffing and the investors' valuation strategies. Sales in our model are constrained by available inventory. Our model yields a semiseparating and semipooling equilibrium contingent on the initial inventory level: When the demand is lower than a threshold that depends on and is below the initial inventory level, the manager pads sales by a part of the excess inventory and releases the inflated sales report. The investors “correct” the reported sales and are able to infer perfectly the firm's value. When the demand reaches or exceeds this threshold, the manager pads any excess inventory to the sales and reports the initial inventory is sold out, which censors large demand realizations. Then the investors only infer the real demand is no less than the threshold and value the firm accordingly by expectation. Channel stuffing can influence the inventory decision, too. We find both over- and underinvestment in the initial inventory can arise in our model. We discuss empirical and managerial implications of our findings.

This paper was accepted by Paul H. Zipkin, operations and supply chain management.
The Impact of Founders' Professional-Education Background on the Adoption of Open Science by For-Profit Biotechnology Firms
Authors: Ding Waverly W.
Published: December 2010

This paper investigates the effect of founders' professional-education background on the adoption of an open-science technology strategy, using a sample of 512 young biotechnology firms. After controlling for founders' prior work experience and other organizational and environmental factors, I find that firms with proportionally more Ph.D.-holding entrepreneurs on the founding team have a higher probability of adopting open science. In addition, founders' educational background can mitigate the constraint of organizational environments on strategy. A crowded technological niche provides a more challenging environment for firms to implement open science, due to higher scooping risks. The deterrent effect, however, of such a high-risk environment is smaller among firms founded by proportionally more Ph.D.-holding entrepreneurs. There is also some evidence of a stronger effect of founders' educational background on open science in an institutional environment in which open science has yet to become the industry norm. This finding is consistent with and complements the growing body of research that emphasizes the importance of entrepreneurial background in developing knowledge about new-venture strategy and structure.

This paper was accepted by Olav Sorenson, organizations.
A Framework of Peak Load Pricing with Strategic Firms
Authors: Zöttl Gregor
Published: December 2010

We analyze firms' investment incentives in markets where demand at spot markets is fluctuating and storability of the output is limited. Firms will then find it optimal to invest in a differentiated portfolio of technologies in order to serve fluctuating demand. For optimal behavior of firms, this has been analyzed in the so-called peak load pricing literature—cf. Crew and Kleindorfer [Crew, M., P. Kleindorfer. 1986. The Economics of Public Utility Regulation. MIT Press, Cambridge, MA]. We analyze the case of strategically behaved firms. We derive the equilibrium of the investment game and compare it to the benchmark case of optimal investment. We find that strategic firms have an incentive to overinvest in base load technologies but choose total capacities, which are too low from a welfare point of view.
Network Design and Allocation Mechanisms for Carrier Alliances in Liner Shipping
Authors: Agarwal Richa , Ergun Özlem
Published: December 2010

Many real-world systems operate in a decentralized manner, where individual operators interact with varying degrees of cooperation and self motive. In this paper, we study transportation networks that operate as an alliance among different carriers. In particular, we study alliance formation among carriers in liner shipping. We address tactical problems such as the design of large-scale networks (that result from integrating the service networks of different carriers in an alliance) and operational problems such as the allocation of limited capacity on a transportation network among the carriers in the alliance. We utilize concepts from mathematical programming and game theory and design a mechanism to guide the carriers in an alliance to pursue an optimal collaborative strategy. The mechanism provides side payments to the carriers, as an added incentive, to motivate them to act in the best interest of the alliance while maximizing their own profits. Our computational results suggest that the mechanism can be used to help carriers form sustainable alliances.