bluuebunny/crossref_metadata_2025 huggingface dataset:
La coloration de l'information dans l'efficience semi forte
Authors: Boya Christophe , Monino Jean-Louis
Published: October 2011

Résumé Cet article contribue à la littérature sur la forme semi forte de l’efficience. Il étudie l’impact des informations exogènes issues de la presse médiatique sur les cours de Bourse. Il rapproche la coloration de l’information exogène à l’actif sous-jacent afin d’examiner les variations boursières. L’application empirique montre que les informations permettent d’anticiper les mouvements de prix. Il remet en cause les fondements de l’efficience. Les résultats montrent la possibilité de prévoir à court terme les rendements. Codes JEL : C14, D83, G14
Repenser la valeur économique pour concevoir d'autres modes de développement
Authors: Perrin Jacques
Published: October 2011

Résumé Les catastrophes écologiques, la croissance des inégalités sociales provoquées par le mode de développement initié par les pays industrialisés nous obligent à essayer de concevoir d’autres modes de développement. Pour cela il nous faut repenser le système de références qui a servi à concevoir notre mode actuel de développement. Ce dernier s’inscrivant dans la pensée néo-classique a été construit notamment sur l’idée que la valeur des biens et des services est égale à leur prix et que la richesse d’un pays, d’un territoire est égale à la valeur monétaire de ce qu’il produit ou de ce qu’il peut acquérir. Pour arrêter de croire qu’on est plus riche en consommant plus il faut remettre la valeur économique au centre de la recherche en sciences économiques. C’est en remettant en avant la différenciation entre valeur et valeur d’échange qu’il est possible de mieux comprendre la différence entre développement et croissance d’un pays, d’un territoire donné. L’objectif de cet article est de suggérer des orientations de recherche sur ce que devrait être la valeur économique pour prendre en compte les défis écologiques et sociaux de ce début de millénaire. Codes JEL : O40, D46, O40, E13, Q01, I30
Les nouveaux défis de l'industrie en France
Authors: Ranque Denis , d'Iribarne Alain , Loos François , Dehecq Jean-François
Published: October 2011

Résumé La volonté de rendre notre territoire national compétitif ne restera qu’une incantation si de nombreux défis ne sont pas relevés. Mais la France ne manque pas de ressources et dans tous les secteurs, des talents prêts à se lancer à l’aventure rencontrent le succès.
Coopaname
Authors: Veyer Stéphane
Published: October 2011

Résumé Coopaname permet à des chômeurs de créer leur emploi avec un statut de salarié au sein d’une coopérative qui les accompagne dans le développement de leur activité, leur permettant ainsi d’échapper à la solitude du créateur d’entreprise tout en leur assurant une protection sociale.
Lorsque le compteur d'eau donne la mesure du monde indien
Authors: Amiraly Akil
Published: October 2011

Résumé Entre 2000 et 2006, Veolia Eau a installé le compteur d’eau dans un quartier de Chennai, en Inde du Sud. Cette expérience fut un échec. Mais en Inde comme ailleurs, les usagers se disent prêts à payer le service de l’eau, dès lors qu’il est de qualité et proposé à un prix acceptable.
Pour une vision de l'entreprise dans son écosystème
Authors: Pénicaud Muriel
Published: October 2011

Résumé En ces temps de crise et d’exigences environnementales accrues, comment concilier efficacité économique et performance sociale ? Danone choisit résolument la voie de la responsabilité sociale par des innovations radicales dans les rapports que l’entreprise entretient avec son écosystème.
A Cytosolic Phospholipase A2-Initiated Lipid Mediator Pathway Induces Autophagy in Macrophages
Authors: Qi Hai-Yan , Daniels Mathew P. , Liu Yueqin , Chen Li-Yuan , Alsaaty Sara , Levine Stewart J. , Shelhamer James H.
Published: October 2011

Autophagy delivers cytoplasmic constituents to autophagosomes and is involved in innate and adaptive immunity. Cytosolic phospholipase (cPLA2)-initiated proinflammatory lipid mediator pathways play a critical role in host defense and inflammation. The crosstalk between the two pathways remains unclear. In this study, we report that cPLA2 and its metabolite lipid mediators induced autophagy in the RAW246.7 macrophage cell line and in primary monocytes. IFN-γ–triggered autophagy involves activation of cPLA2. Cysteinyl leukotrienes D4 and E4 and PGD2 also induced these effects. The autophagy is independent of changes in mTOR or autophagic flux. cPLA2 and lipid mediator-induced autophagy is ATG5 dependent. These data suggest that lipid mediators play a role in the regulation of autophagy, demonstrating a connection between the two seemingly separate innate immune responses, induction of autophagy and lipid mediator generation.
IL-23 Is Required for Long-Term Control of Mycobacterium tuberculosis and B Cell Follicle Formation in the Infected Lung
Authors: Khader Shabaana A. , Guglani Lokesh , Rangel-Moreno Javier , Gopal Radha , Fallert Junecko Beth A. , Fountain Jeffrey J. , Martino Cynthia , Pearl John E. , Tighe Michael , Lin Yin-yao , Slight Samantha , Kolls Jay K. , Reinhart Todd A. , Randall Troy D. , Cooper Andrea M.
Published: October 2011

IL-23 is required for the IL-17 response to infection with Mycobacterium tuberculosis, but is not required for the early control of bacterial growth. However, mice deficient for the p19 component of IL-23 (Il23a−/−) exhibit increased bacterial growth late in infection that is temporally associated with smaller B cell follicles in the lungs. Cxcl13 is required for B cell follicle formation and immunity during tuberculosis. The absence of IL-23 results in decreased expression of Cxcl13 within M. tuberculosis-induced lymphocyte follicles in the lungs, and this deficiency was associated with increased cuffing of T cells around the vessels in the lungs of these mice. Il23a−/− mice also poorly expressed IL-17A and IL-22 mRNA. These cytokines were able to induce Cxcl13 in mouse primary lung fibroblasts, suggesting that these cytokines are likely involved in B cell follicle formation. Indeed, IL-17RA–deficient mice generated smaller B cell follicles early in the response, whereas IL-22–deficient mice had smaller B cell follicles at an intermediate time postinfection; however, only Il23a−/− mice had a sustained deficiency in B cell follicle formation and reduced immunity. We propose that in the absence of IL-23, expression of long-term immunity to tuberculosis is compromised due to reduced expression of Cxcl13 in B cell follicles and reduced ability of T cells to migrate from the vessels and into the lesion. Further, although IL-17 and IL-22 can both contribute to Cxcl13 production and B cell follicle formation, it is IL-23 that is critical in this regard.
Local Delivery of GM-CSF Protects Mice from Lethal Pneumococcal Pneumonia
Authors: Steinwede Kathrin , Tempelhof Ole , Bolte Kristine , Maus Regina , Bohling Jennifer , Ueberberg Bianca , Länger Florian , Christman John W. , Paton James C. , Ask Kjetil , Maharaj Shyam , Kolb Martin , Gauldie Jack , Welte Tobias , Maus Ulrich A.
Published: October 2011

The growth factor GM-CSF has an important role in pulmonary surfactant metabolism and the regulation of antibacterial activities of lung sentinel cells. However, the potential of intra-alveolar GM-CSF to augment lung protective immunity against inhaled bacterial pathogens has not been defined in preclinical infection models. We hypothesized that transient overexpression of GM-CSF in the lungs of mice by adenoviral gene transfer (Ad-GM-CSF) would protect mice from subsequent lethal pneumococcal pneumonia. Our data show that intra-alveolar delivery of Ad-GM-CSF led to sustained increased pSTAT5 expression and PU.1 protein expression in alveolar macrophages during a 28-d observation period. Pulmonary Ad-GM-CSF delivery 2–4 wk prior to infection of mice with Streptococcus pneumoniae significantly reduced mortality rates relative to control vector-treated mice. This increased survival was accompanied by increased inducible NO synthase expression, antibacterial activity, and a significant reduction in caspase-3–dependent apoptosis and secondary necrosis of lung sentinel cells. Importantly, therapeutic treatment of mice with rGM-CSF improved lung protective immunity and accelerated bacterial clearance after pneumococcal challenge. We conclude that prophylactic delivery of GM-CSF triggers long-lasting immunostimulatory effects in the lung in vivo and rescues mice from lethal pneumococcal pneumonia by improving antibacterial immunity. These data support use of novel antibiotic-independent immunostimulatory therapies to protect patients against bacterial pneumonias.
The Pathogenic Th17 Cell Response to Major Schistosome Egg Antigen Is Sequentially Dependent on IL-23 and IL-1β
Authors: Shainheit Mara G. , Lasocki Krzysztof W. , Finger Eduardo , Larkin Bridget M. , Smith Patrick M. , Sharpe Arlene H. , Dinarello Charles A. , Rutitzky Laura I. , Stadecker Miguel J.
Published: October 2011

CBA/J mice infected with the helminth Schistosoma mansoni develop severe CD4 T cell-mediated hepatic granulomatous inflammation against parasite eggs associated with a robust Th17 cell response. We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by transgenic T cells, whereas exogenous IL-23 or IL-1β reconstituted their ability to produce IL-17 when stimulated by syngeneic IL-12p40–deficient dendritic cells. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1β. Significantly, schistosome-infected IL-12p40–deficient or IL-1R antagonist-treated CBA/J mice developed markedly reduced hepatic immunopathology with a dampened egg Ag-specific IL-17 response. These results demonstrate that the IL-23–IL-1–IL-17 axis has a central role in the development of severe schistosome egg-induced immunopathology.
Impaired B Cell Development in the Absence of Krüppel-like Factor 3
Authors: Vu Thi Thanh , Gatto Dominique , Turner Vivian , Funnell Alister P. W. , Mak Ka Sin , Norton Laura J. , Kaplan Warren , Cowley Mark J. , Agenès Fabien , Kirberg Jörg , Brink Robert , Pearson Richard C. M. , Crossley Merlin
Published: October 2011

Krüppel-like factor 3 (Klf3) is a member of the Klf family of transcription factors. Klfs are widely expressed and have diverse roles in development and differentiation. In this study, we examine the function of Klf3 in B cell development by studying B lymphopoiesis in a Klf3 knockout mouse model. We show that B cell differentiation is significantly impaired in the bone marrow, spleen, and peritoneal cavity of Klf3 null mice and confirm that the defects are cell autonomous. In the bone marrow, there is a reduction in immature B cells, whereas recirculating mature cells are noticeably increased. Immunohistology of the spleen reveals a poorly structured marginal zone (MZ) that may in part be caused by deregulation of adhesion molecules on MZ B cells. In the peritoneal cavity, there are significant defects in B1 B cell development. We also report that the loss of Klf3 in MZ B cells is associated with reduced BCR signaling strength and an impaired ability to respond to LPS stimulation. Finally, we show increased expression of a number of Klf genes in Klf3 null B cells, suggesting that a Klf regulatory network may exist in B cells.
Programmed Cell Death 1 Suppresses B-1b Cell Expansion and Long-Lived IgG Production in Response to T Cell-Independent Type 2 Antigens
Authors: Haas Karen M.
Published: October 2011

B-1b cells play a key role in producing Abs against T cell-independent type 2 Ags. However, the factors regulating Ab production by this unique B cell subset are not well understood. In this study, a detailed analysis of the B cell response to 2,4,6-trinitrophenol (TNP)-Ficoll was performed using normal mice. TNP-Ficoll delivered i.p. or i.v. induced rapid Ag-specific B-1b cell activation, expansion, isotype switching, and plasmablast/plasma cell differentiation. Ag-specific B-1b cell numbers peaked at day 5 and then gradually declined in the spleen but remained elevated in the peritoneal cavity beyond 40 d postimmunization. In addition to expressing CD43, CD44, and CD86, Ag-activated B-1b cells transiently expressed programmed cell death 1 (PD-1), which functionally suppressed BCR-induced B-1b cell in vitro proliferation when additional costimulatory signals were lacking. Inhibiting PD-1:PD-1 ligand interactions during TNP-Ficoll immunization significantly enhanced Ag-specific B-1b cell expansion and the frequency of IgG isotype switching and plasmablast/plasma cell differentiation. Remarkably, PD-1 mAb blockade during the first week following immunization resulted in significantly increased numbers of both splenic and bone marrow Ag-specific IgG3-secreting cells, but not IgM-secreting cells, at both early (day 5) and late (week 6) time points. Moreover, Ag-specific serum IgG3 levels, as well as IgG2c, IgG2b, and IgA levels, remained significantly elevated in PD-1 mAb-treated mice relative to control Ab-treated mice for ≥6 wk postimmunization. Thus, PD-1:PD-1 ligand interactions occurring shortly after initial T cell-independent type 2 Ag encounter play a critical role in suppressing Ag-specific B-1b cell expansion and the development of long-term IgG-producing bone marrow and spleen cells.
Nonsteroidal antiinflammatory drug intake according to the Assessment of SpondyloArthritis International Society Score in clinical trials evaluating tumor necrosis factor blockers: Example of etanercept in advanced ankylosing spondylitis
Authors: Dougados Maxime , Braun Jurgen , Szanto Sandor , Combe Bernard , Geher Pal , Leblanc Véronique , Logeart Isabelle
Published: October 2011

Objective

To evaluate the interest of the Assessment of SpondyloArthritis international Society (ASAS) nonsteroidal antiinflammatory drug (NSAID) score as a quality indicator and a potential outcome measure in clinical studies.

Methods

We used data from patients with active, advanced, axial ankylosing spondylitis refractory to NSAIDs. The study design was a 12‐week, randomized, placebo‐controlled period followed by a 12‐week open‐label extension. The ASAS‐NSAID score was collected during 3 periods of interest (i.e., the 12 weeks preceding baseline, the 12 weeks of the placebo‐controlled trial, and the 12 weeks of the open‐label trial).

Results

For the 82 enrolled patients, the mean ± SD ASAS‐NSAID score at baseline was similar between the 2 groups: 93 ± 76 and 74 ± 54 in the etanercept and placebo groups, respectively. There was no significant change in the ASAS‐NSAID score during the first part of the trial, as recommended by the protocol. There was a statistically significant decrease in the ASAS‐NSAID score during the second part of the trial with a relevant effect size (−0.56) in the placebo to etanercept group.

Conclusion

This study confirms the feasibility and simplicity of the ASAS‐NSAID score and suggests that such a score be integrated in all studies in spondylarthritis either to check the quality of the observed data (i.e., intergroup baseline characteristics) or to evaluate the NSAID‐sparing effect of other therapies.
Cyclopia: An epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research
Authors: Orioli Iêda M. , Amar Emmanuelle , Bakker Marian K. , Bermejo‐Sánchez Eva , Bianchi Fabrizio , Canfield Mark A. , Clementi Maurizio , Correa Adolfo , Csáky‐Szunyogh Melinda , Feldkamp Marcia L. , Landau Danielle , Leoncini Emanuele , Li Zhu , Lowry R. Brian , Mastroiacovo Pierpaolo , Morgan Margery , Mutchinick Osvaldo M. , Rissmann Anke , Ritvanen Annukka , Scarano Gioacchino , Szabova Elena , Castilla Eduardo E.
Published: October 2011

Cyclopia is characterized by the presence of a single eye, with varying degrees of doubling of the intrinsic ocular structures, located in the middle of the face. It is the severest facial expression of the holoprosencephaly (HPE) spectrum. This study describes the prevalence, associated malformations, and maternal characteristics among cases with cyclopia. Data originated in 20 Clearinghouse (ICBDSR) affiliated birth defect surveillance systems, reported according to a single pre‐established protocol. A total of 257 infants with cyclopia were identified. Overall prevalence was 1 in 100,000 births (95%CI: 0.89–1.14), with only one program being out of range. Across sites, there was no correlation between cyclopia prevalence and number of births (r = 0.08; P = 0.75) or proportion of elective termination of pregnancy (r = −0.01; P = 0.97). The higher prevalence of cyclopia among older mothers (older than 34) was not statistically significant. The majority of cases were liveborn (122/200; 61%) and females predominated (male/total: 42%). A substantial proportion of cyclopias (31%) were caused by chromosomal anomalies, mainly trisomy 13. Another 31% of the cases of cyclopias were associated with defects not typically related to HPE, with more hydrocephalus, heterotaxia defects, neural tube defects, and preaxial reduction defects than the chromosomal group, suggesting the presence of ciliopathies or other unrecognized syndromes. Cyclopia is a very rare defect without much variability in prevalence by geographic location. The heterogeneous etiology with a high prevalence of chromosomal abnormalities, and female predominance in HPE, were confirmed, but no effect of increased maternal age or association with twinning was observed. © 2011 Wiley Periodicals, Inc.
Shift work at young age is associated with increased risk for multiple sclerosis
Authors: Hedström Anna Karin , Åkerstedt Torbjörn , Hillert Jan , Olsson Tomas , Alfredsson Lars
Published: October 2011

Objective:

Environmental factors play a prominent role in multiple sclerosis (MS) etiology. The aim of this study was to investigate the potential association between shift work and MS risk, which has previously never been investigated.

Methods:

This report is based on 2 population‐based, case–control studies, 1 with incident cases (1,343 cases, 2,900 controls) and 1 with prevalent cases (5,129 cases, 4,509 controls). Using logistic regression, the occurrence of MS among subjects who have been exposed to shift work at various ages was compared with that of those who have never been exposed by calculating the odds ratio (OR) with a 95% confidence interval (CI).

Results:

In both studies, there was a significant association between working shift at a young age and occurrence of MS (OR, 1.6; 95% CI, 1.2–2.1 in the incidence study and OR, 1.3; 95% CI, 1.0–1.6 in the prevalence study). In the incident study, the OR of developing MS was 2.0 (95% CI, 1.2–3.6) among those who had worked shifts for 3 years or longer before age 20 years, compared with those who had never worked shifts. The OR for the corresponding comparison in the prevalent study was 2.1 (95% CI, 1.3–3.4).

Interpretation:

The observed association between shift work at a young age and occurrence of MS in 2 independent studies strengthens the notion of a true relationship. Consequences of shift work such as circadian disruption and sleep restriction are associated with disturbed melatonin secretion and enhanced proinflammatory responses and may thus be part of the mechanism behind the association. ANN NEUROL 2011;
Identification and characterization of a novel corticotropin‐releasing hormone‐binding protein (CRH‐BP) gene from Chinese honeybee (Apis cerana cerana)
Authors: Liu Li , Yu Xiaoli , Meng Fei , Guo Xingqi , Xu Baohua
Published: October 2011

Corticotropin‐releasing hormone‐binding protein (CRH‐BP) is an essential secreted glycoprotein for coordinating the neuroendocrine responses to stress by binding either CRHs or its related peptides. A novel CRH‐BP gene AccCRH‐BP from Apis cerana cerana was identified and characterized. Its genomic DNA was consisted of seven exons and six introns, and shared high similarity with the homologous members from other insects and vertebrates. Homologous and phylogenetic analysis indicated that AccCRH‐BP was highly conserved, suggesting the maintenance of conservative structure might be necessary for its biological function. Real‐time quantitative PCR revealed that AccCRH‐BP was highly expressed in pupa and adult, especially in the head of pupa. However, there was no expression in larval stage. Furthermore, the transcripts of AccCRH‐BP in the brain of honeybees were induced by exposure to environmental stresses including UV‐light, heat, and cold. The expression level of AccCRH‐BP in workers or queens was significantly higher than that of drones. Additionally, analysis of 5′‐flanking region of AccCRH‐BP revealed a number of putative development and stress transcription factor‐binding sites. These data suggest that AccCRH‐BP may play important roles in the regulation of honeybee development, and in the central nervous system of the brain to regulate the neuroendocrine stress responses. © 2011 Wiley Periodicals, Inc.
Wnt signaling genes of murine chromosome 15 are involved in sex‐affected pathways of inflammatory arthritis
Authors: Kudryavtseva Elena , Forde Toni S. , Pucker Andrew D. , Adarichev Vyacheslav A.
Published: October 2011

Objective

Sex disparities in rheumatoid arthritis (RA) are well documented despite the lack of any known major RA susceptibility genes mapped to sex chromosomes. Murine chromosome 15 carries the sex‐affected Pgia8 locus that mediates proteoglycan‐induced arthritis, and homologous human loci are associated with RA. This study was undertaken to identify genes/mechanisms implicated in sex disparities in arthritis.

Methods

Gene expression analysis was performed using RNA isolated from the paws of male and female Pgia8‐congenic mice with collagen antibody–induced arthritis. Results were corroborated by reverse transcription–polymerase chain reaction, and mice were also studied prior to disease onset. Ingenuity Pathways Analysis of the expression patterns and gene functions was used to discover locus‐specific and sex‐affected signature transcripts.

Results

We found that the Pgia8 locus regulates antibody‐mediated inflammatory arthritis differently in males and females. In Pgia8‐congenic males, arthritis severity was 30% less (P < 0.005) than in wild‐type males, but the antiinflammatory effect was similar in wild‐type and congenic females. Transcriptome analysis indicated that 12 genes within the locus were significantly dysregulated in arthritic joints of congenic mice; expression of these genes was also sex specific. The genes that correlated most highly with arthritis severity included those for collagen triple‐helix repeat–containing 1 (Cthrc1), metalloproteinase (Adamts12), R‐spondin (Rspo2), and syndecan (Sdc2) (r = 0.87–0.91). The level of Cthrc1 message also correlated with that of the genes for the proinflammatory cytokines interleukin‐1β and interleukin‐6.

Conclusion

These results indicate that sex‐specific disparities in RA are linked to transcriptional regulation of genes involved in cartilage degradation (Adamts12) and canonical and noncanonical Wnt signaling (Cthrc1, Rspo2, Sdc2).
Disorders in angiogenesis and redox pathways are main factors contributing to the progression of rheumatoid arthritis: A comparative proteomics study
Authors: Wang Jian‐Guang , Xu Wei‐Dong , Zhai Wei‐Tao , Li Yan , Hu Jie‐Wei , Hu Bo , Li Ming , Zhang Ling , Guo Wei , Zhang Jian‐Peng , Wang Liang‐Hua , Jiao Bing‐Hua
Published: October 2011

Objective

To clarify the pathogenesis of rheumatoid arthritis (RA) by comparing protein expression in fibroblast‐like synoviocytes (FLS) from patients with RA with that in FLS from normal subjects, using proteomics analysis.

Methods

Proteins extracted from primary cultures of FLS obtained from 50 patients with RA and 10 normal subjects were analyzed by automated 2‐dimensional nano–electrospray ionization liquid chromatography tandem mass spectometry. Differentially expressed proteins were screened by 2‐sample t‐test (P < 0.05) and fold change (>1.5), based on the bioinformatics analysis. The expression of vasculature development–related proteins (Thy‐1, connective tissue growth factor [CTGF], and thrombospondin 1 [TSP‐1]) and redox‐related proteins (superoxide dismutase 2 [SOD2]) in synovial tissue was confirmed by real‐time polymerase chain reaction and Western blotting. The effect of Thy‐1 and CTGF knockdown on Thy‐1, CTGF, TSP‐1, and vascular endothelial growth factor (VEGF) was analyzed by RNA interference experiments.

Results

According to the criteria of having >1 unique peptide per protein present and a false discovery rate of ≤5%, 1,060 proteins were identified from patients with RA, and 1,292 proteins were identified from normal subjects, from which 100 differentially expressed proteins were screened out from the RA proteins. Of these, 46 proteins were up‐regulated, and the remaining 54 proteins were down‐regulated. Gene ontology and pathway analyses showed that 6 vasculature development–related proteins were up‐regulated, including Thy‐1, CTGF, and TSP‐1, while 11 redox‐related proteins were down‐regulated, including SOD2. The results were consistent with those obtained using mass spectrometry. Thy‐1, VEGF, CTGF, and TSP‐1 were down‐regulated after Thy‐1 knockdown, and VEGF and CTGF were down‐regulated after CTGF knockdown. Recombinant human CTGF could enhance proliferation and Transwell migration of human umbilical vein endothelial cells.

Conclusion

Up‐regulation of vasculature development–related proteins and down‐regulation of redox‐related proteins in FLS are predominant factors that may contribute to the pathogenesis of RA.
Reducing the Linear Perception of Nonlinearity: Use of a Physical Representation
Authors: Dutt Varun , Gonzalez Cleotilde
Published: October 2011

Research shows that while judging accumulations of quantities over time (e.g., money in a bank account or CO2 in Earth's atmosphere), people assume that the shape of the accumulation is similar to the shape of the inflow (i.e., people rely on a correlation heuristic). Relying on the correlation heuristic is particularly worrisome for Earth's climate, as judging the CO2 accumulation according to its emissions (inflow) would underestimate the actual (nonlinear) increase. This misperception undermines the seriousness of climate problem and results in wait‐and‐see behavior. We report two experiments where the effectiveness of a physical representation is compared with graphical and text representations in reducing people's underestimation of nonlinear accumulation in different contexts and problems. A physical representation presents an accumulation using a picture that works as a metaphor. In the first experiment, participants drew the shape of an accumulation over time relying on physical or graphical representations in one of two contexts: carbon dioxide and marbles. Although the participants underestimated the accumulation in both contexts, underestimations were reduced in the physical representation compared with the graphical representation. In the second experiment, we extended the evaluation of physical representations against both text and graphical representations in two different climate problems (with linearly increasing or decreasing inflow). Again, underestimations of the accumulation were reduced in the physical representation compared with the other two representations, regardless of the nature of the problem. We discuss implications of using the physical representation for improving people's estimates of nonlinear CO2 accumulation. Copyright © 2011 John Wiley & Sons, Ltd.
Developmental toxicology—new directions workshop: refining testing strategies and study designs
Authors: C. Brannen Kimberly , Fenton Suzanne E. , Hansen Deborah K. , Harrouk Wafa , Kim James H. , Shuey Dana
Published: October 2011

In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee held a two‐day workshop entitled “Developmental Toxicology—New Directions.” The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode‐of‐action; and (5) special considerations in reproductive testing for biologics. The presentations were followed by discussion by the presenters and attendees. Much of the discussion focused on aspects of refining current animal testing strategies, including use of toxicokinetic data, dose selection, tiered/triggered testing strategies, species selection, and use of alternative animal models. Another major area of discussion was use of non‐animal‐based testing paradigms, including how to define a “signal” or adverse effect, translating in vitro exposures to whole animal and human exposures, validation strategies, the need to bridge the existing gap between classical toxicology testing and risk assessment, and development of new technologies. Although there was general agreement among participants that the current testing strategy is effective, there was also consensus that traditional methods are resource‐intensive and improved effectiveness of developmental toxicity testing to assess risks to human health is possible. This article provides a summary of the session's presentations and discussion and describes some key areas that warrant further consideration. Birth Defects Res (Part B) 92:404–412, 2011. © 2011 Wiley Periodicals, Inc.
Enhanced stability and activity of cellulase in an ionic liquid and the effect of pretreatment on cellulose hydrolysis
Authors: Bose Sayantan , Barnes Charles A. , Petrich Jacob W.
Published: October 2011

We discuss the hydrolysis of cellulose using a pure cellulase: endo‐1,4‐β‐D‐glucanase (EG) from the fungus, Aspergillus niger, in buffer, the pure ionic liquid (IL), tris‐(2‐hydroxyethyl)‐methylammonium methylsulfate (HEMA), and various mixtures of the two at different temperatures. Steady‐state fluorescence and absorbance studies were performed to monitor the stability and activity of EG using cellulose azure as the substrate. EG attains its highest activity at 45°C in buffer and denatures at ∼55°C. On the other hand, HEMA imparts substantial stability to the enzyme, permitting the activity to peak at 75°C. The relative roles of temperature, viscosity, pH, polarity, and the constituent ions of the ILs on the hydrolysis reaction are examined. It is demonstrated that pretreatment of cellulose with ILs such as BMIM Cl, MIM Cl, and HEMA results in more rapid conversion to glucose than hydrolysis with cellulose that is not pretreated. The percent conversion to glucose from pretreated cellulose is increased when the temperature is increased from 45 to 60°C. Two different ILs are used to increase the efficiency of cellulose conversion to glucose. Cellulose is pretreated with BMIM Cl. Subsequent hydrolysis of the pretreated cellulose in 10–20% solutions of HEMA in buffer provides higher yields of glucose at 60°C. Finally, to our knowledge, this is the first study dealing with a pure endoglucanase from commercial A. niger. This enzyme not only shows higher tolerance to ILs, such as HEMA, but also has enhanced thermostability in the presence of the IL. Biotechnol. Bioeng. 2012; 109:434–443. © 2011 Wiley Periodicals, Inc.
HPLC‐UV analytical method for determination of pizotifen after in vitro transdermal diffusion studies
Authors: Serna‐Jiménez C. E. , del Rio Sancho S. , Calatayud‐Pascual M. A. , Balaguer‐Fernández C. , Femenía‐Font A. , López‐Castellano A. , Merino V.
Published: October 2011

Pizotifen malate is an antihistamine and serotonin inhibitor used in the preventive treatment of migraine and eating disorders. A simple, rapid, accurate and precise high‐performance liquid chromatography (HPLC) method involving ultraviolet detection was validated for the quantitative analysis of pizotifen malate in samples from in vitro transdermal diffusion studies. The method was validated for specificity, linearity, accuracy, precision, limit of detection, limit of quantification and robustness. Drug stability in the solution was also determined under different conditions. Separation was carried out using a 250 × 4.0 mm Kromasil® C18 column at room temperature. The detector response, fitted at 254 nm, was found to be linear in a concentration range between 0.24 and 24.0 µg/mL. The limit of detection was 0.02 µg/mL and the limit of quantification was 0.07 µg/mL. Finally, in vitro transdermal diffusion of pizotifen malate was characterized using the validated HPLC method. Copyright © 2011 John Wiley & Sons, Ltd.
Adoption of the Balanced Scorecard: A Contingency Variables Analysis
Authors: Hendricks Kevin , Hora Manpreet , Menor Larry , Wiedman Christine
Published: October 2011

Our study investigates the adoption of the Balanced Scorecard (BSC) as a strategic planning system. We empirically examine the firm‐level factors—business‐level strategy, firm size, environmental uncertainty, investment in intangible assets, and prior performance— that are posited to differentiate BSC adopters from nonadopters. Drawing on a sample of Canadian firms and utilizing both survey and archival data, we find that BSC adopters (a) are more likely to follow a Prospector or Analyzer business strategy, (b) are significantly larger, (c) exhibit significantly higher environmental uncertainty than nonadopters, and (d) have weaker prior performance. Copyright © 2011 ASAC. Published by John Wiley & Sons, Ltd.
Selective detection of histologically aggressive prostate cancer
Authors: Williams Stephen B. , Salami Simpa , Regan Meredith M. , Ankerst Donna P. , Wei John T. , Rubin Mark A. , Thompson Ian M. , Sanda Martin G.
Published: October 2011

BACKGROUND:

Limited survival benefit and excess treatment because of prostate‐specific antigen (PSA) screening in randomized trials suggests a need for more restricted selection of prostate biopsy candidates by discerning risk of histologically aggressive versus indolent cancer before biopsy.

METHODS:

Subjects undergoing first prostate biopsy enrolled in a multicenter, prospective cohort of the National Cancer Institute Early Detection Research Network (N = 635) were analyzed to develop a model for predicting histologically aggressive prostate cancers. The control arm of the Prostate Cancer Prevention Trial (N = 3833) was used to validate the generalization of the predictive model.

RESULTS:

The Early Detection Research Network cohort was comprised of men among whom 57% had no cancer, 14% had indolent cancer, and 29% had aggressive cancer. Age, body mass index, family history of prostate cancer, abnormal digital rectal examination (DRE), and PSA density (PSAD) were associated with aggressive cancer (all P < .001). The Early Detection Research Network model outperformed PSA alone in predicting aggressive cancer (area under the curve [AUC] = 0.81 vs 0.71, P < .01). Model validation in the Prostate Cancer Prevention Trial cohort accurately identified men at low (<10%) risk of aggressive cancer for whom biopsy could be averted (AUC = 0.78; 95% confidence interval, 0.75‐0.80). Under criteria from the Early Detection Research Network model, prostate biopsy can be restricted to men with PSAD >0.1 ng/mL/cc or abnormal DRE. When PSAD is <0.1 ng/mL/cc, family history or obesity can identify biopsy candidates.

CONCLUSIONS:

A predictive model incorporating age, family history, obesity, PSAD, and DRE elucidates criteria whereby ¼ of prostate biopsies can be averted while retaining high sensitivity in detecting aggressive prostate cancer. Cancer 2011. © 2011 American Cancer Society.
Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra‐adrenal paragangliomas
Authors: Ayala‐Ramirez Montserrat , Feng Lei , Habra Mouhammed A. , Rich Thereasa , Dickson Paxton V. , Perrier Nancy , Phan Alexandria , Waguespack Steven , Patel Shreyaskumar , Jimenez Camilo
Published: October 2011

BACKGROUND:

The objective of this study was to evaluate the clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic paragangliomas by assessing reductions in tumor size and blood pressure and improvements in overall survival (OS).

METHODS:

The authors retrospectively reviewed the medical records of patients with metastatic pheochromocytomas‐sympathetic paragangliomas who had received chemotherapy at The University of Texas MD Anderson Cancer Center.

RESULTS:

Clinical benefit and OS were assessed. Of 54 patients who received chemotherapy, 52 patients were evaluable for response. Seventeen patients (33%) experienced a response, which was defined as decreased or normalized blood pressure/decreased number and dosage of antihypertensive medications and/or reduced tumor size after the first chemotherapy regimen. The median OS was 6.4 years (95% confidence interval [CI], 5.2‐16.4 years) for responders and 3.7 years (95% CI, 3.0‐7.5 years) for nonresponders. Among the patients who had synchronous metastatic disease, a positive response at 1 year after the start of chemotherapy was associated with a trend toward longer OS (log‐rank test; P = .095). In a multivariate Cox proportional hazards model, the effect of response to chemotherapy on OS was significant (hazard ratio, 0.22; 95% CI, interval: 0.05‐1.0; P = .05). All responders had received dacarbazine and cyclophosphamide. Vincristine was included for 14 responders, and doxorubicin was included for 12 responders. The clinical factors that predicted response to chemotherapy could not be identified.

CONCLUSIONS:

The current results indicted that chemotherapy may decrease tumor size and facilitate blood pressure control in approximately 33% of patients with metastatic pheochromocytoma‐sympathetic paraganglioma. These patients exhibited longer survival. Cancer 2011. © 2011 American Cancer Society.
The clinical, research, and social value of autopsy after any cancer death
Authors: Spunt Sheri L. , Vargas Sara O. , Coffin Cheryl M. , Skapek Stephen X. , Parham David M. , Darling Joan , Hawkins Douglas S. , Keller Charles
Published: October 2011

Collection of tumor tissue at autopsy can provide valuable tumor specimens to advance research for many types of cancer. Autopsy also has many other medical, scientific, and social benefits and should be encouraged in patients who are dying of cancer.
Immunohistochemical identification and synaptic inputs to the diffuse bipolar cell type DB1 in macaque retina
Authors: Puthussery Theresa , Gayet‐Primo Jacqueline , Taylor W. Rowland , Haverkamp Silke
Published: October 2011

Detailed analysis of the synaptic inputs to the primate DB1 bipolar cell has been precluded by the absence of a suitable immunohistochemical marker. Here we demonstrate that antibodies for the EF‐hand calcium‐binding protein, secretagogin, strongly label the DB1 bipolar cell as well as a mixed population of GABAergic amacrine cells in the macaque retina. Using secretagogin as a marker, we show that the DB1 bipolar makes synaptic contact with both L/M as well as S‐cone photoreceptors and only minimal contact with rod photoreceptors. Electron microscopy showed that the DB1 bipolar makes flat contacts at both triad‐associated and nontriad‐associated positions on the cone pedicle. Double labeling with various glutamate receptor subunit antibodies failed to conclusively determine the subunit composition of the glutamate receptors on DB1 bipolar cells. In the IPL, DB1 bipolar cell axon terminals expressed the glycine receptor, GlyRα1, at sites of contact with AII amacrine cells, suggesting that these cells receive input from the rod pathway. J. Comp. Neurol. 519:3640–3656, 2011. © 2011 Wiley‐Liss, Inc.
Generating smooth surface meshes from multi‐region medical images
Authors: d'Otreppe Vinciane , Boman Romain , Ponthot Jean‐Philippe
Published: October 2011

Thanks to advances in medical imaging technologies and numerical methods, patient‐specific modelling is more and more used to improve diagnosis and to estimate the outcome of surgical interventions. It requires the extraction of the domain of interest from the medical scans of the patient, as well as the discretisation of this geometry. However, extracting smooth multi‐material meshes that conform to the tissue boundaries described in the segmented image is still an active field of research. We propose to solve this issue by combining an implicit surface reconstruction method with a multi‐region mesh extraction scheme. The surface reconstruction algorithm is based on multi‐level partition of unity implicit surfaces, which we extended to the multi‐material case. The mesh generation algorithm consists in a novel multi‐domain version of the marching tetrahedra. It generates multi‐region meshes as a set of triangular surface patches consistently joining each other at material junctions. This paper presents this original meshing strategy, starting from boundary points extraction from the segmented data to heterogeneous implicit surface definition, multi‐region surface triangulation and mesh adaptation. Results indicate that the proposed approach produces smooth and high‐quality triangular meshes with a reasonable geometric accuracy. Hence, the proposed method is well suited for subsequent volume mesh generation and finite element simulations. Copyright © 2011 John Wiley & Sons, Ltd.
Formulation of buffer energy and experimental results of energy factor of DC–DC converters
Authors: Shi Zhang Hai , Cheng Ka Wai Eric , Ho Siu Lau
Published: October 2011

Two concepts of buffer energy and energy factor for switched‐mode power converters are proposed and examined. They can describe the nonactive power as well as predict and evaluate the performance of DC–DC converters. The concepts can also find usage in both DC and AC systems. The energy factors of six basic topologies of DC–DC converter have been studied, and they can be used to compare the performance of different topologies. It can be shown that both buffer energy and energy factor provide an alternative understanding of the energy processes in DC–DC converters. Experimental results demonstrate that energy factors and buffer energy can be measured. The measured results for some basic converters are consistent with the theoretical values. Buffer energy, energy factor, and their related concepts proposed in this article have promising application in the design of DC–DC converters. Copyright © 2011 John Wiley & Sons, Ltd.
The extracellular region of Lrp4 is sufficient to mediate neuromuscular synapse formation
Authors: Gomez Andrea M. , Burden Steven J.
Published: October 2011

Neuromuscular synapse formation requires an exchange of signals between motor neurons and muscle. Agrin, supplied by motor neurons, binds to Lrp4 in muscle, stimulating phosphorylation of MuSK and recruitment of a signaling complex essential for synapse‐specific transcription and anchoring of key proteins in the postsynaptic membrane. Lrp4, like the LDLR and other Lrp‐family members, contains an intracellular region with motifs that can regulate receptor trafficking, as well as assembly of an intracellular signaling complex. Here, we show that the intracellular region of Lrp4 is dispensable for Agrin to stimulate MuSK phosphorylation and clustering of acetylcholine receptors in cultured myotubes. Moreover, muscle‐selective expression of a Lrp4‐CD4 chimera, composed of the extracellular and transmembrane regions of Lrp4 and the intracellular region of CD4, rescues neuromuscular synapse formation and the neonatal lethality of lrp4 mutant mice, demonstrating that Lrp4, lacking the Lrp4 intracellular region, is sufficient for presynaptic and postsynaptic differentiation. Developmental Dynamics 240:2626–2633, 2011. © 2011 Wiley Periodicals, Inc.
A clonal model for human CD8+ regulatory T cells: Unrestricted contact‐dependent killing of activated CD4+ T cells
Authors: Hu Dan , Liu Xia , Zeng Wanyong , Weiner Howard L. , Ritz Jerome
Published: October 2011

Previous studies in murine systems have demonstrated that CD8+ Treg cells down‐regulate immune responses in vivo through suppressing activated CD4+ T cells. Here we describe novel regulatory CD8+ T‐cell clones isolated from healthy human peripheral blood following in vitro stimulation with autologous Epstein–Barr virus (EBV)‐specific CD4+ T cells. TCR activation of CD4+ target T cells was required for CD8+ Treg cells to exert suppressive activity, which was mediated through lysis of CD4+ targets in a cell contact‐dependent manner. Suppression was independent of Foxp3 expression in CD8+ Treg cells, HLA compatibility between CD8+ Treg cells and CD4+ target cells and antigen‐specificity of CD4+ target T cells. CD8+ Treg clones expressed CD3 and a variety of TCR Vβ chains as well as CD56, CD69, CD62L and CD95 but did not express CD16, CD161, CXCR4 and CCR7. When used together, antibodies specific for CD11a/CD18 and CD8 inhibited suppressive activity of CD8+ Treg clones. The ability to establish clonal CD8+ T cells that maintain regulatory function in vitro will facilitate further studies to define this population in vivo and to identify the mechanisms used for recognition and suppression of activated target cells.
Intestinal macrophages – specialised adaptation to a unique environment
Authors: Bain Calum C. , Mowat Allan McI.
Published: October 2011

Interest in intestinal mononuclear phagocytes (MPs), both DCs and macrophages (Mφs), has exploded in the recent years. In this Viewpoint we will detail how resident intestinal lamina propria (LP) Mφs possess distinctive properties that reflect adaptation to a unique microenvironment. They play quite different roles in the normal and inflamed mucosa and, as we will show, the existing paradigms of differentiated Mφ subsets and of ‘resident’ versus ‘inflammatory’ monocytes based on other tissues may not apply to the gut. Strategies for targeting Mφs as a means of dampening intestinal inflammation will need to take account of these unique characteristics.
Inflammatory signaling in macrophages: Transitions from acute to tolerant and alternative activation states
Authors: Ivashkiv Lionel B.
Published: October 2011

Acute inflammatory activation of macrophages by Toll‐like and related receptors is characterized by transient activation of MAPK‐, NF‐κB‐ and IRF‐mediated signaling pathways and expression of pro‐inflammatory genes. This activation state is inherently unstable and often transitions into a state of ‘tolerance’ characterized by diminished signaling, repressive chromatin modifications, and an alternative gene expression program. This Viewpoint describes signaling and epigenetic mechanisms associated with transition to tolerant states, which are proposed to correspond to alternative activation states programmed by the original inflammatory stimuli.
Macrophage activation governs schistosomiasis‐induced inflammation and fibrosis
Authors: Barron Luke , Wynn Thomas A.
Published: October 2011

Macrophages regulate the initiation, maintenance, and resolution of chronic inflammatory responses and their function depends on their activation status. Studies in mice infected with the helminth parasite Schistosoma mansoni have been particularly helpful in defining the in vivo function of classically and alternatively activated macrophages (AAMϕs). These studies have shown that AAMϕs protect mice from acute and chronic S. mansoni infection through distinct mechanisms, which are discussed in this Viewpoint.