bluuebunny/crossref_metadata_2025 huggingface dataset:
Why cities cannot be sustainable: Governance and planning for Istanbul
Authors: Unalan Dilek
Published: June 2011

In many countries, inward investment has become a central aim of local development policy and cities have come to be conceived of as the true natural business units in today’s economy. However, while some cities have managed to retain a healthy urban core in the face of suburban growth, many others have not. In those cities which could develop in a more sustainable way redevelopment of brownfield properties, in-fill projects, more affordable housing developments, and the move to renovate older homes have been further signs of sustaining development within existing city boundaries. In other cities, the wave of urban construction has failed to deliver sustainable land use and environmental protection as their natural resources and ecosystems have been degraded by modern industrial systems. The comparison of these urban contexts may shed light on governing and planning modes raised by sustainable development. This study addresses spatial and environmental patterns of governance. It questions the relationships between urban governance and planning with an aim to understand why cities cannot be sustainable. To achieve this, it focuses on Istanbul, Turkey where local planning authorities have been carrying out urban transformation projects since the 2000s, and examines how various urban transformations have been perceived and conducted by local planners.
Male and Female Child Murderers
Authors: Sellers Brian G. , Heide Kathleen M.
Published: June 2011

Recent U.S. cases of murders by children below age 11 have captured national headlines. A review of the literature reveals that little is known about this population of juvenile homicide offenders (JHOs). Most studies on juvenile murderers have used small clinical samples, focused on adolescents, and concentrated on male offenders. Studies that have used Supplementary Homicide Report (SHR) data have found significant gender differences among juveniles below 18 years arrested for murder. This study investigated gender differences among 226 juvenile murderers ages 6 through 10 involved in single-victim incidents using bivariate and multivariate statistical techniques. Consistent with previous research, bivariate analyses revealed gender differences with respect to the type of weapon used, age of the victim, relationship to the victim, and circumstances of the crime. Logistic regression analysis identified female JHOs as more likely to use a knife, kill a family member, and kill a victim below age 5, when compared with male JHOs. From these findings, profiles of young male and female JHOs can be drawn. The article concludes with a discussion of the study’s implications for prevention and treatment. The authors recommend that future research in gender differences among young children focus on examining psychological, neurological, and sociological variables not included in the SHR data set.
Digital photoelasticity – A comprehensive review
Authors: Ramesh K , Kasimayan T , Neethi Simon B
Published: June 2011

Digital photoelasticity has rapidly progressed in the last few years and has matured into an industry-friendly technique. This review thematically classifies all the developments in digital photoelasticity and highlights the relative merits and drawbacks of the various techniques. The overall objective is to provide enough information and guidance to allow an end-user to make an informed choice on the type of technique to be used in a particular situation.
The through-the-thickness measurement of residual stress in a thick welded steel compact tension specimen by the contour method
Authors: Richter-Trummer V , de Castro P M S T
Published: June 2011

Compact tension specimens are widely used for fatigue crack growth characterization. It is well known that when using this type of specimen for welded samples, residual stresses affect the crack growth behaviour, in particular, reducing the crack growth rate when the initial notch is parallel to the weldment. Several approaches have been used to characterize the residual stress field in welded compact tension specimens, including traditional destructive relaxation-based methods, as well as non-destructive diffraction-based techniques. The problem with the approaches presented so far is that the former do not provide through-the-thickness results, whereas the latter, although capable of providing through-the-thickness measurements, are only available in very few facilities worldwide. The interest in thick welded samples, where substantial through-the-thickness variations of residual stress fields are to be expected, leads to the need for a full-field characterization. In the present work, the residual stress perpendicular to the crack growth path in two welded steel compact tension specimens was measured by the contour method, an emerging destructive method. A full surface map of the residual stresses was obtained. This full field information on the residual stress distribution reveals substantial through-the-thickness variations. High compressive stresses were found in the centre of both specimens. The compact tension specimen with the crack plane in the centre of the weld bead presented slightly higher compressive residual stresses. The strong variation of the stress field, both in the longitudinal as well as in the through-the-thickness directions, emphasizes the need for full-field residual stress measurements for the correct interpretation of fatigue crack growth tests when using this type of specimen.
“I’m Not a Victim, She’s an Abuser”
Authors: Durfee Alesha
Published: June 2011

Previous research analyzing masculinity and domestic violence has focused on men’s accounts of the violence they have committed; relatively little research has focused on men’s accounts of victimization. This article critically examines how men negotiate the competing discourses of victimization, hegemonic masculinity, and stereotypes about domestic violence when filing for a domestic violence protection order against a woman partner. Three themes related to gender and victimization emerged from the men’s narratives. First, the men’s descriptions of the violence they had experienced focused on their power and control over their intimate partner. Second, the men described their active resistance to the abuse but were careful to note that their actions were not “abusive” and that they were not the “abusers.” Finally, although most of the men described both verbal and physical abuse, most did not express a fear of their partner. I discuss the results of this analysis in the context of the recent increase in men claiming victimization in a number of realms.
Time to stand up for democracy
Authors: Dear Jeremy
Published: June 2011

The retiring general secretary of the National Union of Journalists offers solutions to flaws he sees on the media landscape
Telling Things Apart
Authors: Lakens Daniël , Schneider Iris K. , Jostmann Nils B. , Schubert Thomas W.
Published: June 2011

People use spatial distance to talk and think about differences between concepts, and it has been argued that using space to think about different categories provides a scaffold for the categorization process. In the current study, we investigated the possibility that the distance between response keys can influence categorization times in binary classification tasks. In line with the hypothesis that distance between response keys can facilitate response selection in a key-press version of the Stroop task, our results showed that responses on incongruent Stroop trials were significantly facilitated when participants performed the Stroop task with response keys located far apart, compared with when they performed the task with response keys located close together. These results support the idea that the spatial structuring of response options facilitates categorizations that require cognitive effort, and that people can incorporate environmental structures such as spatial distance in their thought processes. Keeping your hands apart might actually help to keep things apart in your mind.
Parameter identification and optimization in piezoelectric energy harvesting: analytical relations, asymptotic analyses, and experimental validations
Authors: Erturk A , Inman D J
Published: June 2011

Mathematical analyses of distributed-parameter piezoelectric energy harvester equations are presented for parameter identification and optimization. The focus is placed on the single-mode voltage and vibration frequency response functions (FRFs) per translational base acceleration. Asymptotic trends of the voltage output and the tip displacement FRFs are investigated and expressions are obtained for the extreme conditions of the load resistance. The relationship between the linear voltage asymptotes and the optimal load resistance is discussed. Resonance frequencies of the voltage and the tip displacement FRFs are obtained accounting for the presence of mechanical losses. Closed-form expressions are extracted for the optimal electrical loads of maximum power generation at the short-circuit and open-circuit resonance frequencies of the voltage FRF. Analytical relations are given also for the identification of modal mechanical damping both from the voltage and the vibration FRFs using a single data point. Vibration attenuation and amplification due to resonance frequency shift is also addressed. An experimental case study is presented to validate some of the major equations derived here.
On the optimum parameters of a device for harvesting energy from running and walking
Authors: Ramlan R , Brennan M J , Mace B R
Published: June 2011

This paper investigates the feasibility of using an energy harvesting device tuned such that its natural frequency coincides with higher harmonics of the input to capture energy from walking or running human motion more efficiently. The paper starts by reviewing the concept of a linear resonant generator for a tonal frequency input and then derives an expression for the power harvested for an input with several harmonics. The amount of power harvested is estimated numerically using measured data from human subjects. Assuming that the input is periodic, the signal is reconstructed using a Fourier series before being used in the simulation. It is found that although the power output depends on the input frequency, the choice of tuning the natural frequency of the device to coincide with a particular higher harmonic is restricted by the amount of damping that is needed to maximize the amount of power harvested, as well as to comply with the size limit of the device. It is also found that it is not feasible to tune the device to match the first few harmonics when the size of the device is small, because a large amount of damping is required to limit the motion of the mass.
Anatomic Study of Distribution, Numbers, and Size of Lymph Nodes in Mesorectum in Indians: A Autopsy Study
Authors: Thakur Satish , Somashekar Uday , Shiv Kumar Chandrakar  , Sharma Dhananjaya
Published: June 2011

This study was conducted to find the number, size, and distribution of the lymph nodes in the mesorectum in fresh cadavers without rectal cancer in Indians and to compare fat clearance method versus manual dissection of lymph nodes in terms of efficacy of lymph node yield. Thirty fresh cadavers underwent total mesorectal excision (TME) by midline incision. TME specimen was divided transversely (upper, middle, and lower thirds), and then further divided radially into 4 equal areas and the right lateral, left lateral, and posterior areas were taken for lymph node harvesting. In the first 15 cases (group A), lymph nodes were dissected manually from each of 9 areas. Number and diameters of harvested nodes were noted, and specimens were histopathologically examined. In the next 15 cases (group B), fat clearing technique was used, and the procedure was repeated. Mean number of lymph nodes recovered per cadaver was 6.2 (SD = 1.3; range, 5 to 9, group A = 5.86 ± 1.24, group B = 6.60 ± 1.29, P = .126) and mean size of the lymph node was 2.1 mm (SD = 0.38; range, 2 to 8 mm). Size and numbers of nodes in all the areas were similar between the 2 groups except in lower third, where smaller nodes were identified in greater numbers in group B. Manual dissection is an effective technique for node harvesting after TME, except for very small nodes found in the lower third of mesorectum. Accurate pathological examination of TME specimen is mandatory to avoid understaging of disease.
The Emerging Role of Public-Private Partnerships in Megaproject Delivery
Authors: Little Richard G.
Published: June 2011

As civil infrastructure projects have grown in scale and scope, their cost has increased accordingly. As a result, we have entered what has been termed the era of the infrastructure megaproject; those that typically cost more than US$1 billion (oftentimes much more) and also have major impacts on communities, the environment, and public finance. Although constructed works of enormous cost and impact have existed since ancient times and have often been financed by the private sector, what distinguishes the modern megaproject is its unfortunate association with huge delays in delivery time and large cost overruns. This article examines some of the reasons why megaprojects have become synonymous with poor cost and schedule performance and suggests that innovative project delivery methods, broadly termed public—private partnerships (PPP or P3), have the potential to improve project performance by better integration of the project delivery organization in the allocation and management of risk.
Measuring Infrastructure Performance
Authors: Oswald Michelle , Li Qiang , McNeil Sue , Trimbath Susanne
Published: June 2011

Infrastructure systems are the foundation for economic growth and productivity. Business and commerce depend on roadways, waterways, pipelines, electricity lines, and broadband connections to transport goods, gain access, provide services, communicate, and efficiently function. Despite the importance of infrastructure, empirical economists have been hindered by the lack of infrastructure performance measures. The U.S. Chamber of Commerce is supporting the development of a national index to measure and understand infrastructure performance. In contrast to established infrastructure assessments which rely on dollars spent or counting highway miles, this index applies a rigorous, repeatable, and universal methodology to quantify infrastructure performance. This article documents the methodology for developing a national infrastructure index and the application for one sector: transportation. The integration of the analytic hierarchy process (AHP) into the methodology as a mechanism to weight performance indicators is discussed as well as the challenges faced in constructing a Transportation Performance Index.
Bending behaviors of metallic sandwich plates with a sheared dimple core under simply supported loading
Authors: Seong DY , Jung CG , Yang DY , Nam GH , Ahn DG
Published: June 2011

In this study, the bending responses of metallic sandwich plates with a sheared dimple core were investigated through the 3-point bending tests and dynamic plane bending tests. It was experimentally shown from the uniaxial tensile tests that the yield and tensile strengths of the brazed face sheet were weaker than those of the welded face sheet. A mild steel sheared dimple core was fabricated by the sectional forming process and then bonded with DP590 face sheets by multi-point resistance welding. Analysis for large deformation of a sandwich plate subject to 3-point bending was carried out, where frictional work was considered and a face sheet was treated as a rigid-plastic material based on Hollomon’s flow rule. Load—deflection curves and the deformed shapes of the finite element method computations and the experiments were efficiently predicted by the proposed analysis. The effect of frictional work on the peak load and energy absorption increases as the bending angle increases. The dynamic bending responses of the sandwich plates, such as the effect of a deformed shape, failure mode, energy absorption and absorption ratio were compared with those of a high-strength steel sheet. It was demonstrated that a bendable sandwich plate was stronger construction than a high-strength steel sheet under the tested conditions, despite the weight reduction and weaker properties.
Ignoring the problem: Spatial strategies for ameliorating social contradictions in early South Asian Buddhism
Authors: Fogelin Lars
Published: June 2011

In the last 50 years, anthropologists have come to understand that cultures are fractured and fractious rather than carefully balanced systems. In this time, many anthropologists, often relying on theoretical understandings of power, have sought to explain how social fissures and social contradictions are resolved, exploited or synthesized. In this article, I propose another way people accommodate irresolvable social contradictions — they ignore them. Through a study of the architectural layout of early Buddhist worship halls in South Asia (c.250 BCE—100 CE), this article examines spatial strategies for ignoring intractable social contradictions. Ancient Buddhist monks ameliorated contradictions between the need for individual asceticism and communalism by spatially separating the simultaneous experience of contradictory ritual acts.
Using the Internet in Pursuit of Public Sexual Encounters
Authors: Downing Martin J.
Published: June 2011

The current study investigated a subgroup of 112 men who have sex with men who use the Internet in search of partners for sex venue encounters to understand what types of venues they frequent and whether their behaviors are associated with an increased risk of HIV/STI transmission. An initial cluster analysis revealed two patterns of Internet use—low and high frequency—among these men. Although frequency of Internet use to find partners for venue encounters did not cluster with venue attendance, there was a trend among high-frequency Internet users to attend gyms, public bathrooms, and sex clubs more than low-frequency users. Furthermore, high-frequency users attended more venues, preferred venues where multiple partners can be found, and were marginally more likely to engage in unprotected anal sex across venues compared with low-frequency users. Knowing that some venue users initiate venue encounters on the Internet may be useful in targeting appropriate HIV/STI interventions.
Perceptions of Testicular Cancer and Testicular Self-Examination Among College Men
Authors: Rovito Michael J. , Gordon Thomas F. , Bass Sarah Bauerle , DuCette Joseph
Published: June 2011

Testicular self-exam (TSE) is an important tool to prevent late-stage diagnosis of testicular cancer (TC). However, most young men remain unaware of their risk for TC despite a growing number of interventions promoting knowledge and awareness of the disease. Of those interventions, very few discuss perceived vulnerability, perceived value of health promotion, and/or preference for informational materials as viable predictors of behavioral change. In this study, 300 university males were surveyed on their perceptions of vulnerability, perceived value of health promotion methods, TC/TSE knowledge, and preference for health promotional information. The results indicated that men were generally unaware of TC and were unsure of their risk of developing the disease. Participants reported very positive responses to questions about the value of health promotion methods, particularly TSE, and indicated a high intention to perform health promotion behaviors. Most important, participants noted that they preferred personalized, tailored information to learn about TC and TSE. Significant predictors of intention to perform TSE include knowledge and awareness of TC/TSE, perceived value of health promotion, and attitudes. Significant predictors of promotional tool preferences differed among generalized pamphlets, personalized messages, and group training sessions. The authors recommend that researchers tailor promotional messages in TC/TSE awareness campaigns with an individual’s preference for promotional tool.
Overview of a semi-stochastic filtering approach for residual life estimation with applications in condition based maintenance
Authors: Wang W
Published: June 2011

Maintenance policies include break-down-based maintenance, time-based maintenance, and condition-based maintenance. The advances in condition monitoring techniques have made condition-based maintenance a popular and increasingly important choice. With the increased use of condition monitoring information, there is obviously a need for appropriate decision support in plant maintenance planning utilizing available condition monitoring information. However, compared with the extensive literature on diagnosis, relatively little research has been done on the prognosis side of condition-based maintenance. In plant prognosis, a key, but often uncertain, quantity to be modelled is the residual life prediction based on available condition information to date. This paper overviews a semi-stochastic filtering-based residual life prediction approach for the monitored items in condition-based maintenance and introduces the associated applications. First the role of residual life prediction in condition-based maintenance decision making is demonstrated, which highlights the need for such a prediction. Then a detailed discussion is presented of the semi-stochastic filtering models developed for residual life prediction, the extensions made, and the case applications applied to. Finally the results of a comparative study between the semi-stochastic filtering based model and another popular model using empirical data are briefly given. The results show that the filtering-based approach is better in terms of prediction accuracy and cost effectiveness.
Guilt-Induced Self-Punishment as a Sign of Remorse
Authors: Nelissen Rob M. A.
Published: June 2011

Why do people engage in self-punishment when they feel guilty? This article aims to bridge discrepant views that portray guilt either as an adaptive social emotion that is vital to the maintenance of social relations or as a maladaptive emotion that produces a host of negative self-directed responses. An experiment investigating the impact of various audience conditions on self-punishment tendencies suggested that even the negative self-directed responses that characterize certain episodes of guilt may originally serve an adaptive social function by acting as signals of remorse.
Opportunities for using non-linear oscillators to enhance energy harvesting from impulsively loaded structures
Authors: Ma T-W
Published: June 2011

In this study, opportunities of using non-linear oscillators for enhanced energy-harvesting performance are explored. Non-linear systems involving a linear impulsively loaded structure, denoted as the source, and a non-linear oscillator, denoted as the harvester, are considered. An approximate method with complex representation is used to analyse the behaviour of the harvester. Energy harvested is assumed to be converted to electricity through electromagnetic induction and dissipated on resistive load. Thus, the electromechanical coupling is modelled with equivalent viscous damping. It is found that there is a generalized resonant condition under which the harvester absorbs significant amounts of energy from the source. It is shown that as a special case of the generalized non-linear resonance, linear resonance sets the upper bound performance while, when there is significant frequency mismatch, a device designed with proper non-linearity may harvest more energy than its linear counterpart.
Exploring the parametric amplification phenomenon for energy harvesting
Authors: Daqaq M F , Bode D
Published: June 2011

Due to inherent system nonlinearities, many vibratory excitation sources possess a frequency spectrum which contains energy components at multiple integers of the fundamental frequency of the source. In this paper, we theoretically explore the prospect of enhancing the transduction of a vibratory energy harvester (VEH) by utilizing the parametric amplification phenomenon to channel energy from one of these superharmonics, namely the one at twice the fundamental frequency, to a purely resistive load. Towards that end, we consider a piezoelectric cantilevered-type bimorph harvester and show that by tilting the axis of the beam through a proper angle with respect to the direction of excitation, it is possible to utilize a parametric pump to enhance the output power at the fundamental frequency. Percentage improvement in the output power depends on the excitation’s parameters and the mechanical damping ratio. It is observed that when the mechanical damping ratio is small, significant enhancement in the output power is attainable even when the magnitude of the superharmonic is small when compared to the fundamental frequency. Such findings reveal that, under certain conditions, parametric amplification can be utilized to enhance the output power of a VEH especially for microscale applications where the damping ratio can be easily controlled.
Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells
Authors: Merzaban Jasmeen S. , Burdick Monica M. , Gadhoum S. Zeineb , Dagia Nilesh M. , Chu Julia T. , Fuhlbrigge Robert C. , Sackstein Robert
Published: June 2011

Although well recognized that expression of E-selectin on marrow microvessels mediates osteotropism of hematopoietic stem/progenitor cells (HSPCs), our knowledge regarding the cognate E-selectin ligand(s) on HSPCs is incomplete. Flow cytometry using E-selectin-Ig chimera (E-Ig) shows that human marrow cells enriched for HSPCs (CD34+ cells) display greater E-selectin binding than those obtained from mouse (lin−/Sca-1+/c-kit+ [LSK] cells). To define the relevant glycoprotein E-selectin ligands, lysates from human CD34+ and KG1a cells and from mouse LSK cells were immunoprecipitated using E-Ig and resolved by Western blot using E-Ig. In both human and mouse cells, E-selectin ligand reactivity was observed at ∼ 120- to 130-kDa region, which contained two E-selectin ligands, the P-selectin glycoprotein ligand-1 glycoform “CLA,” and CD43. Human, but not mouse, cells displayed a prominent ∼ 100-kDa band, exclusively comprising the CD44 glycoform “HCELL.” E-Ig reactivity was most prominent on CLA in mouse cells and on HCELL in human cells. To further assess HCELL's contribution to E-selectin adherence, complementary studies were performed to silence (via CD44 siRNA) or enforce its expression (via exoglycosylation). Under physiologic shear conditions, CD44/HCELL-silenced human cells showed striking decreases (> 50%) in E-selectin binding. Conversely, enforced HCELL expression of LSK cells profoundly increased E-selectin adherence, yielding > 3-fold more marrow homing in vivo. These data define the key glycoprotein E-selectin ligands of human and mouse HSPCs, unveiling critical species-intrinsic differences in both the identity and activity of these structures.
A switch toward angiostatic gene expression impairs the angiogenic properties of endothelial progenitor cells in low birth weight preterm infants
Authors: Ligi Isabelle , Simoncini Stéphanie , Tellier Edwige , Vassallo Paula Frizera , Sabatier Florence , Guillet Benjamin , Lamy Edouard , Sarlon Gabrielle , Quemener Cathy , Bikfalvi Andreas , Marcelli Maxime , Pascal Alain , Dizier Blandine , Simeoni Umberto , Dignat-George Françoise , Anfosso Francine
Published: June 2011

Low birth weight (LBW) is associated with increased risk of cardiovascular diseases at adulthood. Nevertheless, the impact of LBW on the endothelium is not clearly established. We investigate whether LBW alters the angiogenic properties of cord blood endothelial colony forming cells (LBW-ECFCs) in 25 preterm neonates compared with 25 term neonates (CT-ECFCs). We observed that LBW decreased the number of colonies formed by ECFCs and delayed the time of appearance of their clonal progeny. LBW dramatically reduced LBW-ECFC capacity to form sprouts and tubes, to migrate and to proliferate in vitro. The angiogenic defect of LBW-ECFCs was confirmed in vivo by their inability to form robust capillary networks in Matrigel plugs injected in nu/nu mice. Gene profile analysis of LBW-ECFCs demonstrated an increased expression of antiangiogenic genes. Among them, thrombospondin 1 (THBS1) was highly expressed at RNA and protein levels in LBW-ECFCs. Silencing THBS1 restored the angiogenic properties of LBW-ECFCs by increasing AKT phosphorylation. The imbalance toward an angiostatic state provide a mechanistic link between LBW and the impaired angiogenic properties of ECFCs and allows the identification of THBS1 as a novel player in LBW-ECFC defect, opening new perspectives for novel deprogramming agents.
Association of natural anti-platelet factor 4/heparin antibodies with periodontal disease
Authors: Greinacher Andreas , Holtfreter Birte , Krauel Krystin , Gätke Daniela , Weber Claudia , Ittermann Till , Hammerschmidt Sven , Kocher Thomas
Published: June 2011

Platelet factor 4 (PF4) and heparin (H) form PF4/H complexes, the target of the immune reaction in heparin-induced thrombocytopenia (HIT). HIT seems to be a secondary immune response as anti-PF4/H-IgG antibodies occur as early as day 4 of heparin treatment. This study investigated whether prevalent infections such as periodontitis may induce the PF4/H immune response as: (1) natural anti-PF4/H Abs are present in the normal population; (2) PF4 bound to bacteria exposes the same antigen(s) as PF4/H complexes; and (3) sepsis induces PF4/H Abs in mice. We found PF4 bound to periodontal pathogens (Aggregatibacter actinomycetemcomitans; Porphyromonas gingivalis) enabling subsequent binding of human anti-PF4/H Abs. The association of natural PF4/H Abs and periodontitis was assessed in a case-control study, enrolling individuals with natural anti-PF4/H Abs (n = 40 matched pairs), and in the cross-sectional population-based Study of Health in Pomerania (SHIP; n = 3500). Both studies showed a robust association between periodontitis and presence of anti-PF4/H Abs independent of inflammation markers (case-control study: lowest vs highest tertile, odds ratio, 7.12 [95% confidence interval, 1.73-46.13; P = .005]; SHIP study, ptrend ≤ 0.001). Thus, preimmunization to PF4/bacteria complexes by prevalent infections, for example, periodontitis, likely explains the presence of natural anti-PF4/heparin Abs and the early occurrence of anti-PF4/H-IgG in HIT.
Matrix metalloproteinases in tuberculosis
Authors: Elkington P.T. , Ugarte-Gil C.A. , Friedland J.S.
Published: June 2011

Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route andMycobacterium tuberculosismust drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB.
Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3
Authors: Borget I. , Cadranel J. , Pignon J-P. , Quoix E. , Coudert B. , Westeel V. , Dansin E. , Madelaine J. , Madroszyk A. , Friard S. , Daniel C. , Morin F. , Chouaid C. ,   the ERMETIC Collaborative Group
Published: June 2011

Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-typeEGFRor unknown status received docetaxel), compared with initiation with no patient selection (strategy reference).

A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed.

The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to €5,020 and €5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results.

The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds.
The two tryptophans of β2-microglobulin have distinct roles in function and folding and might represent two independent responses to evolutionary pressure
Authors: Raimondi Sara , Barbarini Nicola , Mangione Palma , Esposito Gennaro , Ricagno Stefano , Bolognesi Martino , Zorzoli Irene , Marchese Loredana , Soria Cristina , Bellazzi Riccardo , Monti Maria , Stoppini Monica , Stefanelli Mario , Magni Paolo , Bellotti Vittorio
Published: June 2011

Background

We have recently discovered that the two tryptophans of human β2-microglobulin have distinctive roles within the structure and function of the protein. Deeply buried in the core, Trp95 is essential for folding stability, whereas Trp60, which is solvent-exposed, plays a crucial role in promoting the binding of β2-microglobulin to the heavy chain of the class I major histocompatibility complex (MHCI). We have previously shown that the thermodynamic disadvantage of having Trp60 exposed on the surface is counter-balanced by the perfect fit between it and a cavity within the MHCI heavy chain that contributes significantly to the functional stabilization of the MHCI. Therefore, based on the peculiar differences of the two tryptophans, we have analysed the evolution of β2-microglobulin with respect to these residues.

Results

Having defined the β2-microglobulin protein family, we performed multiple sequence alignments and analysed the residue conservation in homologous proteins to generate a phylogenetic tree. Our results indicate that Trp60 is highly conserved, whereas some species have a Leu in position 95; the replacement of Trp95 with Leu destabilizes β2-microglobulin by 1 kcal/mol and accelerates the kinetics of unfolding. Both thermodynamic and kinetic data fit with the crystallographic structure of the Trp95Leu variant, which shows how the hydrophobic cavity of the wild-type protein is completely occupied by Trp95, but is only half filled by Leu95.

Conclusions

We have established that the functional Trp60 has been present within the sequence of β2-microglobulin since the evolutionary appearance of proteins responsible for acquired immunity, whereas the structural Trp95 was selected and stabilized, most likely, for its capacity to fully occupy an internal cavity of the protein thereby creating a better stabilization of its folded state.
Liposome-based DNA carriers may induce cellular stress response and change gene expression pattern in transfected cells
Authors: Fiszer-Kierzkowska Anna , Vydra Natalia , Wysocka-Wycisk Aleksandra , Kronekova Zuzana , Jarząb Michał , Lisowska Katarzyna Marta , Krawczyk Zdzisław
Published: June 2011

Background

During functional studies on the rat stress-inducibleHspa1b(hsp70.1) gene we noticed that some liposome-based DNA carriers, which are used for transfection, induce its promoter activity. This observation concerned commercial liposome formulations (LA), Lipofectin and Lipofectamine 2000. This work was aimed to understand better the mechanism of this phenomenon and its potential biological and practical consequences.

Results

We found that a reporter gene driven byHspa1bpromoter is activated both in the case of transient transfections and in the stably transfected cells treated with LA. Using several deletion clones containing different fragments ofHspa1bpromoter, we found that the regulatory elements responsible for most efficient LA-driven inducibility were located between nucleotides -269 and +85, relative to the transcription start site. Further studies showed that the induction mechanism was independent of the classical HSE-HSF interaction that is responsible for gene activation during heat stress. Using DNA microarrays we also detected significant activation of the endogenousHspa1bgene in cells treated with Lipofectamine 2000. Several other stress genes were also induced, along with numerous genes involved in cellular metabolism, cell cycle control and pro-apoptotic pathways.

Conclusions

Our observations suggest that i) some cationic liposomes may not be suitable for functional studies onhsppromoters, ii) lipofection may cause unintended changes in global gene expression in the transfected cells.
GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells
Authors: Abrhale Tesfom , Brodie Angela , Sabnis Gauri , Macedo Luciana , Tian Changsheng , Yue Binbin , Serrero Ginette
Published: June 2011

Background

Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+breast cancer cells

Methods

We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined.

Results

GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole.

Conclusion

Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+breast cancer.
Comparative study of clinical grade human tolerogenic dendritic cells
Authors: Naranjo-Gómez M , Raïch-Regué D , Oñate C , Grau-López L , Ramo-Tello C , Pujol-Borrell R , Martínez-Cáceres E , Borràs Francesc E
Published: June 2011

Background

The use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) forin vitroexperiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP (Good Manufacturing Practice) or clinical grade reagents with the aim of defining their use for human cell therapy.

Methods

Tolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-α, IL-β and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced.

Results

Differences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3-tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol-DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-γ) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-γ production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells.

Conclusions

Our results demonstrate contrasting influences of different clinical-grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease.
Assessing causal relationships in genomics: From Bradford-Hill criteria to complex gene-environment interactions and directed acyclic graphs
Authors: Geneletti Sara , Gallo Valentina , Porta Miquel , Khoury Muin J , Vineis Paolo
Published: June 2011

Observational studies of human health and disease (basic, clinical and epidemiological) are vulnerable to methodological problems -such as selection bias and confounding- that make causal inferences problematic. Gene-disease associations are no exception, as they are commonly investigated using observational designs. A rich body of knowledge exists in medicine and epidemiology on the assessment of causal relationships involving personal and environmental causes of disease; it includes seminal causal criteria developed by Austin Bradford Hill and more recently applied directed acyclic graphs (DAGs). However, such knowledge has seldom been applied to assess causal relationships in clinical genetics and genomics, even in studies aimed at making inferences relevant for human health. Conversely, incorporating genetic causal knowledge into clinical and epidemiological causal reasoning is still a largely unexplored area.

As the contribution of genetics to the understanding of disease aetiology becomes more important, causal assessment of genetic and genomic evidence becomes fundamental. The method we develop in this paper provides a simple and rigorous first step towards this goal. The present paper is an example of integrative research, i.e., research that integrates knowledge, data, methods, techniques, and reasoning from multiple disciplines, approaches and levels of analysis to generate knowledge that no discipline alone may achieve.
First construction of infectious clone for newly emerging mutation porcine circovirus type 2 (PCV2) followed by comparison with PCV2a and PCV2b genotypes in biological characteristics in vitro
Authors: Guo Long J , Lu Yue H , Huang Li P , Wei Yan W , Wu Hong L , Liu Chang M
Published: June 2011

Background

Porcine circovirus type 2 (PCV2), the causative agent of postweaning multisystemic wasting syndrome (PMWS), is a serious economic problem in the swine industry. Different genotypes (PCV2a, PCV2b and PCV2d) of the virus are present in the clinical cases in China, and it is necessary to elucidate the pathogenic difference among different genotypes of PCV2. In this study, four strains of different genotypes were isolated, two were ordinary strains and another two were mutation strains, which there are one and two amino acids elongation in the capsid protein (Cap) of PCV2, respectively. Representative strains of different genotypes of the virus were constructed by infectious molecular clone and biological characterization of the rescued viruses were identified in vitro.

Results

Four PCV2 isolates (PCV2a/CL, PCV2b/YJ, PCV2b/JF and PCV2d/BDH) of different genotypes were isolated from the clinical cases of PMWS in China. Four infectious clones of PCV2 were constructed and the rescued viruses were harvested after transfection into PK15 cells. The rescued viruses were verified by nucleotide sequence analysis, morphology of the viruses and immunoperoxidase monolayer assay (IPMA). The rescued viruses propagated stably after consecutive incubation for more than ten passages, and virus propagation reached its peak 72h post infection (PI), and the virus titers were up to 105.7 TCID50/ml. By using neutralizing 1D2 monoclonal antibody (mAb) of PCV2, the antigen capture ELISA showed that only the PCV2a/rCL and PCV2b/rJF strains has immunoreactivity with the 1D2 mAb, however, another two rescued strains (PCV2b/rYJ and PCV2d/rBDH) do not, which indicated the antigenic difference among the rescued viruses of different genotypes. In addition, here is the first report of obtaining the newly emerging PCV2 with mutation in vitro by infectious molecular clone technology.

Conclusions

Conclusions drawn from this study show that PCV2 has prevailing differences in genomic and ORF2 gene length and antigen in swine herds in China. Four representative clones for different genotypes were constructed and rescued, which will facilitate further studies on the pathogenic differences resulting from different subtypes of PCV2.
Effective inhibition of foot-and-mouth disease virus (FMDV) replication in vitro by vector-delivered microRNAs targeting the 3D gene
Authors: Du Junzheng , Gao Shandian , Luo Jihuai , Zhang Guofeng , Cong Guozheng , Shao Junjun , Lin Tong , Cai Xuepeng , Chang Huiyun
Published: June 2011

Background

Foot-and-mouth disease virus (FMDV) causes an economically important and highly contagious disease of cloven-hoofed animals. RNAi triggered by small RNA molecules, including siRNAs and miRNAs, offers a new approach for controlling viral infections. There is no report available for FMDV inhibition by vector-delivered miRNA, although miRNA is believed to have more potential than siRNA. In this study, the inhibitory effects of vector-delivered miRNAs targeting the 3D gene on FMDV replication were examined.

Results

Four pairs of oligonucleotides encoding 3D-specific miRNA of FMDV were designed and selected for construction of miRNA expression plasmids. In the reporter assays, two of four miRNA expression plasmids were able to significantly silence the expression of 3D-GFP fusion proteins from the reporter plasmid, p3D-GFP, which was cotransfected with each miRNA expression plasmid. After detecting the silencing effects of the reporter genes, the inhibitory effects of FMDV replication were determined in the miRNA expression plasmid-transfected and FMDV-infected cells. Virus titration and real-time RT-PCR assays showed that the p3D715-miR and p3D983-miR plasmids were able to potently inhibit the replication of FMDV when BHK-21 cells were infected with FMDV.

Conclusion

Our results indicated that vector-delivered miRNAs targeting the 3D gene efficiently inhibits FMDV replication in vitro. This finding provides evidence that miRNAs could be used as a potential tool against FMDV infection.