bluuebunny/crossref_metadata_2025 huggingface dataset:
14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage
Authors: Maksymowych Walter P , van der Heijde Désirée , Allaart Cornelia F , Landewé Robert , Boire Gilles , Tak Paul P , Gui Yuan , Ghahary Aziz , Kilani Ruhangiz , Marotta Anthony
Published: April 2014

Introduction

The aim of this study was to investigate whether 14-3-3η, a specific isoform of a family of proteins regulating processes such as cellular signalling, activates cell-signalling pathways and induces factors known to contribute to the pathophysiology of rheumatoid arthritis (RA). We also investigated whether 14-3-3η is associated with more severe disease in both early and established RA.

Methods

We investigated the effect of 14-3-3η on the activation of RA-relevant signalling cascades and induction of proinflammatory mediators that contribute to the joint damage process. 14-3-3η titres from 33 patients with early RA (mean RA duration = 1.8 months) and from 40 patients with established RA were measured in serum drawn at the 3-year time point of the Behandel Strategieën study. The relationship between 14-3-3η titres and standard clinical variables was investigated by correlation analysis. The association with radiographic damage and radiographic progression over at least a 2-year period was investigated using univariate and multivariate regression analyses.

Results

14-3-3η activated selected members of the mitogen-activated protein kinase (MAPK) family, mainly extracellular regulated kinase 1/2 and c-Jun kinase, but not p38MAPK. Activation by 14-3-3η, using levels spanning the concentration range found in RA patient serum, resulted in the induction of inflammatory transcripts such as interleukin 1 (IL-1) and IL-6 and factors linked to the joint damage process, such as receptor activator of nuclear factor κB ligand and matrix metalloproteinase 1. Serum 14-3-3η correlated significantly with rheumatoid factor (RF) (r = 0.43) and anticitrullinated protein antibodies (ACPAs) (r = 0.31) in the early RA cohort, but not with C-reactive protein (CRP) or the Disease Activity Score in 28 joints in either cohort. Serum 14-3-3η concentrations were significantly higher in patients with radiographically assessed joint damage and in those who had radiographic progression. By multivariate analysis, we show that 14-3-3η complemented markers such as CRP, RF and ACPA in informing RA radiographic status and/or progression.

Conclusions

Extracellular 14-3-3η activates key signalling cascades and induces factors associated with the pathogenesis of RA at concentrations found in patients with RA, and its expression is higher in patients with radiographic damage and RA progression.
Incorporating Simulated Ground Motion in Seismic Risk Assessment: Application to the Lower Indian Himalayas
Authors: Sørensen Mathilde B. , Lang Dominik H.
Published: April 2014

In this study, the effects of implementing stochastic finite fault ground motion simulations in earthquake hazard and risk assessment are evaluated. The investigations are conducted for the city of Dehradun (Indian Himalayas). We compare two ground motion estimation techniques: a ground motion prediction equation–based technique and a simulation-based technique. The comparison focuses on the differences the techniques imply on earthquake damage and loss estimates. Ground motion simulations are first calibrated against the instrumental recordings of the 1991 Mw 6.8 Uttarkashi earthquake. Afterward, a number of events are considered with different magnitude, distance, and azimuth to the source. Results indicate large differences between ground motion and loss estimates derived by the two methods, especially in the direction of rupture propagation, which persist to 2–2.5 fault lengths distance. It is therefore strongly recommended to consider rupture kinematics and orientation to the test bed when providing ground motion estimates for near-field earthquake loss assessment studies.
Tie Strength, Embeddedness, and Social Influence: A Large-Scale Networked Experiment
Authors: Aral Sinan , Walker Dylan
Published: April 2014

We leverage the newly emerging business analytical capability to rapidly deploy and iterate large-scale, microlevel, in vivo randomized experiments to understand how social influence in networks impacts consumer demand. Understanding peer influence is critical to estimating product demand and diffusion, creating effective viral marketing, and designing “network interventions” to promote positive social change. But several statistical challenges make it difficult to econometrically identify peer influence in networks. Though some recent studies use experiments to identify influence, they have not investigated the social or structural conditions under which influence is strongest. By randomly manipulating messages sent by adopters of a Facebook application to their 1.3 million peers, we identify the moderating effect of tie strength and structural embeddedness on the strength of peer influence. We find that both embeddedness and tie strength increase influence. However, the amount of physical interaction between friends, measured by coappearance in photos, does not have an effect. This work presents some of the first large-scale in vivo experimental evidence investigating the social and structural moderators of peer influence in networks. The methods and results could enable more effective marketing strategies and social policy built around a new understanding of how social structure and peer influence spread behaviors in society.

This paper was accepted by Alok Gupta, special issue on business analytics.
The Fundamentalist Latter Day Saints after the Texas State Raid
Authors: Wright Stuart A. , Richardson James T.
Published: April 2014

This article explores the impact of the 2008 Texas raid on the Fundamentalist Latter Day Saints community near Eldorado called the Yearning for Zion Ranch. We examine some critical post-raid developments and the convictions of prophet Warren Jeffs and ten other key church leaders on charges related to marriages with underage girls. These developments include Jeffs’ efforts to maintain his authority from prison, non-compliance by some members, the emergence of a rival leader, and Texas’ efforts to seize the Yearning for Zion property. The convergence of these developments has introduced a degree of uncertainty and instability within the FLDS community significantly impacting the future trajectory of the movement.
HBO’s Flexible Gold
Authors: Szalay Michael
Published: April 2014

Recent HBO dramas like Game of Thrones, Luck, and The Newsroom do more than generate HBO brand equity—they quantify that equity and determine the conditions under which it might be converted into other kinds of Time Warner equity. These incipiently financial dramas are futures markets that establish rates of conversion between heterogeneous equities and should be understood as functionally equivalent to the class of financial instruments known as derivatives.
Bad Credit
Authors: McClanahan Annie
Published: April 2014

This essay reads twenty-first-century credit scoring against eighteenth- and nineteenth-century forms of credit evaluation. While the latter famously draws its qualitative model of credibility from the novel, and the former predictably describes itself as quantitative and impersonal, in fact the credit score, the social person, and literary character remain significantly entangled. Through a reading of Gary Shteyngart’s Super Sad True Love Story, this essay shows what kinds of persons the practice of credit rating produces.
The Security Aesthetic in Bollywood’s High-Rise Horror
Authors: Ghosh Bishnupriya
Published: April 2014

This essay theorizes a constellation of “high-rise horror” films from contemporary Bollywood as a cinema of apprehension. I elaborate an emergent “techno-aesthetic of security” that plunges spectators into an immersive experience of horror, orienting them to the violence of acute dispossession (of lands and livelihoods) catalyzed by current speculative financial globalization.
Retcon
Authors: Clover Joshua
Published: April 2014

The epistemological rupture proffered by finance in the seventies, seeming to inaugurate a distinct mode of production, is merely a form of appearance that capital’s struggle takes in crisis, beneath which the capitalist economy remains under the sway of the law of value and its source in socially necessary labor time. While narrative fiction has been taken insistently as the relevant literary mode or genre for understanding the motion and particularly the temporality of finance, poetry finally provides a better heuristic for such an understanding and, more substantially, for grasping the motion and dynamic of value moving behind the seeming of finance’s hegemony.
A Strategy to Identify Dominant Point Mutant Modifiers of a Quantitative Trait
Authors: Dove William F , Shedlovsky Alexandra , Clipson Linda , Amos-Landgraf James M , Halberg Richard B , Krentz Kathleen J , Boehm Frederick J , Newton Michael A , Adams David J , Keane Thomas M
Published: April 2014

A central goal in the analysis of complex traits is to identify genes that modify a phenotype. Modifiers of a cancer phenotype may act either intrinsically or extrinsically on the salient cell lineage. Germline point mutagenesis by ethylnitrosourea can provide alleles for a gene of interest that include loss-, gain-, or alteration-of-function. Unlike strain polymorphisms, point mutations with heterozygous quantitative phenotypes are detectable in both essential and nonessential genes and are unlinked from other variants that might confound their identification and analysis. This report analyzes strategies seeking quantitative mutational modifiers of ApcMin in the mouse. To identify a quantitative modifier of a phenotype of interest, a cluster of test progeny is needed. The cluster size can be increased as necessary for statistical significance if the founder is a male whose sperm is cryopreserved. A second critical element in this identification is a mapping panel free of polymorphic modifiers of the phenotype, to enable low-resolution mapping followed by targeted resequencing to identify the causative mutation. Here, we describe the development of a panel of six “isogenic mapping partner lines” for C57BL/6J, carrying single-nucleotide markers introduced by mutagenesis. One such derivative, B6.SNVg, shown to be phenotypically neutral in combination with ApcMin, is an appropriate mapping partner to locate induced mutant modifiers of the ApcMin phenotype. The evolved strategy can complement four current major initiatives in the genetic analysis of complex systems: the Genome-wide Association Study; the Collaborative Cross; the Knockout Mouse Project; and The Cancer Genome Atlas.
Theory and practice of intervention
Authors: Brauer Jurgen
Published: April 2014

The article discusses, first, systems control theory, which tells us how a self-regulating system, for example of social and political peace, should work. Second, it considers the theory of imperfect markets, which tells us just why peace and security frequently fail to be obtained. Third, it discusses collective action theory, which tells us what might be required for collective intervention in another state's affairs to take place. These set the context, fourth, for a new idea - a theory of intervention - that might explain why individual states, rather than a collective of states, intervene or fail to intervene elsewhere. Fifth, to learn whether the practice of intervention appears to follow the theory laid out, descriptive evidence is presented for interventions undertaken by Australia, Canada, India, and New Zealand, 1899 to 2005.
Economic aspects of peacekeeping in Iraq: What went wrong?
Authors: Yousif Bassam
Published: April 2014

Prospects for Iraq's economy are bleak: unemployment remains high and the post-war rebuilding effort has slowed to a trickle, weighed down by chronic instability. Rising oil prices increased GDP in 2004 and 2005. But an oil-induced rise in GDP will not necessarily bring about a general rise in incomes, as the oil sector employs only 1 percent of the labor force. To raise general living standards, oil income needs to be converted into increased employment and output in sectors with high social rates of return. This article reviews key Coalition Provisional Authority post-war policies and their effects, and proposes and discusses a set of alternative policies that would be better suited to improve Iraqi living standards and help secure peace.
Militarization's long shadow: Namibia's legacy of armed violence
Authors: Lamb Guy
Published: April 2014

Reviewing how the legacy of Namibia's armed conflict has influenced its path of post-conflict reconstruction, the article reflects on the limitations and failures of efforts geared toward the fostering of sustainable peace and the consolidation of democracy. It begins with a short history of the Namibian conflict, then details the immediate post- independence period, focusing on peacebuilding and democratic consolidation (or the lack thereof), and concludes by considering the militaristic dimensions of governance and nation-building in Namibia, emphasizing the links between the legacy of armed violence and contemporary life and politics in this southern African country.
Peacekeeping operations: From the birth of the United Nations onward
Authors: Klein Lawrence R.
Published: April 2014

The article reviews proposals to create a United Nations standing armed force as opposed to a rapid reaction force. In either case, to play its optimal role in the future of peacekeeping operations, the U.N. will have to face up to new demands, beyond those contemplated in 1945. Given the resistance in Iraq that has surprised two major powers (the United States and the United Kingdom), it is plausible that a truly collective effort by the U.N., even at higher costs in people and finance, merits serious consideration in order to secure peaceful lives in the world.
Nanoscale Charge Transport Characteristics at Perovskite Interfaces – a Holistic Perspective
Authors: Kraya Ramsey , Kraya Laura
Published: April 2014

Here we investigate how charge transport properties scale down to the nanoscale regime, comparing the properties to standard semiconductor materials and providing a perspective on what it means to device manufacturing. Strontium titanate - the prototypical oxide material - has been widely studied for applications in thermoelectrics, nanoelectronics, catalysis, and other uses. We investigated how charge transport is effected at interfaces to strontium titanate under a wide range of conditions - by varying contact size, interface shape, dopant concentration, surface structures and in various combinations and relate the results to experiments utilizing standard semiconducting materials such as silicon and gallium arsenide. Also, the results of the analysis has wide ranging implications, especially for ferroelectric perovskite materials and serves as the basis for understanding and controlling switching effects - both polarization and oxygen migration based switching.
Countryside biogeography of Neotropical reptiles and amphibians
Authors: Mendenhall Chase D. , Frishkoff Luke O. , Santos-Barrera Georgina , Pacheco Jesús , Mesfun Eyobed , Quijano Fernando Mendoza , Ehrlich Paul R. , Ceballos Gerardo , Daily Gretchen C. , Pringle Robert M.
Published: April 2014

The future of biodiversity and ecosystem services depends largely on the capacity of human‐dominated ecosystems to support them, yet this capacity remains largely unknown. Using the framework of countryside biogeography, and working in the Las Cruces system of Coto Brus, Costa Rica, we assessed reptile and amphibian assemblages within four habitats that typify much of the Neotropics: sun coffee plantations (12 sites), pasture (12 sites), remnant forest elements (12 sites), and a larger, contiguous protected forest (3 sites in one forest). Through analysis of 1678 captures of 67 species, we draw four primary conclusions. First, we found that the majority of reptile (60%) and amphibian (70%) species in this study used an array of habitat types, including coffee plantations and actively grazed pastures. Second, we found that coffee plantations and pastures hosted rich, albeit different and less dense, reptile and amphibian biodiversity relative to the 326‐ha Las Cruces Forest Reserve and neighboring forest elements. Third, we found that the small ribbons of “countryside forest elements” weaving through farmland collectively increased the effective size of a 326‐ha local forest reserve 16‐fold for reptiles and 14‐fold for amphibians within our 236‐km2 study area. Therefore, countryside forest elements, often too small for most remote sensing techniques to identify, are contributing ∼95% of the available habitat for forest‐dependent reptiles and amphibians in our largely human‐dominated study region. Fourth, we found large and pond‐reproducing amphibians to prefer human‐made habitats, whereas small, stream‐reproducing, and directly developing species are more dependent on forest elements. Our investigation demonstrates that tropical farming landscapes can support substantial reptile and amphibian biodiversity. Our approach provides a framework for estimating the conservation value of the complex working landscapes that constitute roughly half of the global land surface, and which are experiencing intensification pressure worldwide.
Masting promotes individual‐ and population‐level reproduction by increasing pollination efficiency
Authors: Moreira Xoaquín , Abdala-Roberts Luis , Linhart Yan B. , Mooney Kailen A.
Published: April 2014

Masting is a reproductive strategy defined as the intermittent and synchronized production of large seed crops by a plant population. The pollination efficiency hypothesis proposes that masting increases pollination success in plants. Despite its general appeal, no previous studies have used long‐term data together with population‐ and individual‐level analyses to assess pollination efficiency between mast and non‐mast events. Here we rigorously tested the pollination efficiency hypothesis in ponderosa pine (Pinus ponderosa), a long‐lived monoecious, wind‐pollinated species, using a data set on 217 trees monitored annually for 20 years. Relative investment in male and female function by individual trees did not vary between mast and non‐mast years. At both the population and individual level, the rate of production of mature female cones relative to male strobili production was higher in mast than non‐mast years, consistent with the predicted benefit of reproductive synchrony on reproductive success. In addition, at the individual level we found a higher conversion of unfertilized female conelets into mature female cones during a mast year compared to a non‐mast year. Collectively, parallel results at the population and individual tree level provide robust evidence for the ecological, and potentially also evolutionary, benefits of masting through increased pollination efficiency.
Research on Production Strategy with Carbon Emissions
Authors: Tang Honglei , Song Guofang
Published: April 2014

This paper mainly studied the influence on the carbon emission permits and trading on the production strategy
for manufacturing enterprises. The enterprises might obtain carbon emission permits in three different ways, i.e.
government quota, market trading and purification treatment. The enterprises must make a tradeoff between them. The
characteristic of purifying cost was analyzed. Then, an optimal production model with carbon emission permits and
trading was established. Finally, a typical numerical experiment was employed to show the influence of the parameters on
optimal production decisions.
Study on the Pressure and Temperature Distribution of Solid-Plug Conveying Element on Centrifugal Extruder
Authors: Jing Zhao , Jing Wang , Shijie Wang
Published: April 2014

In this paper, a new polymer processing machine--- centrifugal extruder is introduced. The pressure and
temperature distribution of centrifugal extruder have been studied by theoretical analysis, which is based on mathematics
and experiments. The results show that the pressure and temperature Distribution can provide the processing of solid-plug
conveying sufficiently and stably, which can prove the industry practicability of centrifugal extruder.
HIV Co-Testing Among Veterans with Chronic Hepatitis C in the
Veterans Health Administration
Authors: Fuller Bret E. , Rodriguez Veronica L. , Linke Alex , Hauser Peter
Published: April 2014

Objective: This retrospective study analyzed the testing rates of individuals enrolled in the Hepatitis C Clinical
Case Registry for the Veterans Health Administration (VHA) in order to determine Human Immunodeficiency Virus
(HIV) co-testing rates for veterans with hepatitis C (HCV). Design: A chart review of 247,006 veterans enrolled in the
National HCV Clinical Case Registry was examined retrospectively. Regression analysis identified factors that increased
the probability of being tested for HIV. Methods: Simple odds ratios and a complex regression were applied to this dataset
to calculate testing incidence and prevalence of HIV. Results: Only approximately one third of veterans with HCV were
tested for HIV and, of these, 13.2% were positive. Sixty eight percent of veterans with HCV were not co-tested for HIV
and within this group there may be a significant number of unidentified cases of HIV. Veterans with severe mental illness,
substance use disorders and marijuana abuse/dependence treatment were more likely to be tested for HIV. Antiviral
therapy for HCV had no impact on likelihood of co-testing prior to treatment initiation. Conclusions: Most veterans with
HCV are not co-tested for HIV despite common risk factors for HIV and HCV infection. Mandatory testing for HIV, at
least among veterans with HCV, as well as identification and removal of barriers to HIV testing within the VHA would
serve to facilitate disease management for veterans in the future.
Incentive structure in team-based learning: graded versus ungraded Group Application exercises
Authors: Deardorff Adam S , Moore Jeremy A , McCormick Colleen , Koles Paul G , Borges Nicole J
Published: April 2014

Purpose: Previous studies on team-based learning (TBL) in medical education demonstrated improved learner engagement, learner satisfaction, and academic performance; however, a paucity of information exists on modifications of the incentive structure of “traditional” TBL practices. The current study investigates the impact of modification to conventional Group Application exercises by examining student preference and student perceptions of TBL outcomes when Group Application exercises are excluded from TBL grades. Methods: During the 2009–2010 and 2010–2011 academic years, 175 students (95.6% response rate) completed a 22-item multiple choice survey followed by 3 open response questions at the end of their second year of medical school. These students had participated in a TBL supplemented preclinical curriculum with graded Group Application exercises during year one and ungraded Group Application exercises during year two of medical school.Results: Chi-square analyses showed significant differences between grading categories for general assessment of TBL, participation and communication, intra-team discussion, inter-team discussion, student perceptions of their own effort and development of teamwork skills. Furthermore, 83.8% of students polled prefer ungraded Group Application exercises with only 7.2% preferring graded and 9.0% indicating no preference.Conclusion: The use of ungraded Group Application exercises appears to be a successful modification of TBL, making it more “student-friendly” while maintaining the goals of active learning and development of teamwork skills.
Mechanism of Thin Layers Graphite Formation by 13C Implantation and Annealing
Authors: Gutierrez Gaelle , Normand François , Aweke Fitsum , Muller Dominique , Speisser Claude , Antoni Frédéric
Published: April 2014

The mechanism of thin layers graphite (TLG) synthesis on a polycrystalline nickel film deposited on SiO2 (300 nm thick)/Si(100) has been investigated by 13C implantation of four equivalent graphene monolayers and annealing at moderate temperatures (450–600 °C). During this process, the implanted 13C segregates to the surface. Nuclear Reaction Analyses (NRA) are used for the first time in the topic of graphene synthesis to separate the isotopes and to determine the 12C and 13C concentrations at each step. Indeed, a significant part of carbon in the TLG also comes from residual 12C carbon absorbed into the metallic matrix. Raman spectroscopy and imaging are used to determine the main location of each carbon isotope in the TLG. The Raman mappings especially emphasize the role of 12C previously present at the surface that first diffuses along grain boundaries. They play the role of nucleation precursors. Around them the implanted 13C or a mixture of bulk 12C–13C aggregate and further precipitate into graphene-like fragments. Graphenization is effective at around 600 °C. These results point out the importance of controlling carbon incorporation, as well as the importance of preparing a uniform nickel surface, in order to avoid heterogeneous nucleation.
Optimum Envelope of a Single-Family House Based on Life Cycle Analysis
Authors: Hamelin Marie-Claude , Zmeureanu Radu
Published: April 2014

This paper describes the methodology used for the life cycle cost (LCC) and life cycle energy (LCE) analyses of the case study house in Quebec, Canada. The TRNSYS energy analysis program is coupled with GenOpt, a general purpose optimization program, for the purpose of this study. The particle swarm optimization (PSO) algorithm is used for the search for the optimum solution. Results show that the optimum levels of insulation should be higher than the reference values, even for the case of LCC analysis. The results are for the most part still valid if electricity costs are assumed to increase below the inflation rate for the duration of the study period.
Functional Identification of Proteus mirabilis eptC Gene Encoding a Core Lipopolysaccharide Phosphoethanolamine Transferase
Authors: Aquilini Eleonora , Merino Susana , Knirel Yuriy , Regué Miguel , Tomás Juan
Published: April 2014

By comparison of the Proteus mirabilis HI4320 genome with known lipopolysaccharide (LPS) phosphoethanolamine transferases, three putative candidates (PMI3040, PMI3576, and PMI3104) were identified. One of them, eptC (PMI3104) was able to modify the LPS of two defined non-polar core LPS mutants of Klebsiella pneumoniae that we use as surrogate substrates. Mass spectrometry and nuclear magnetic resonance showed that eptC directs the incorporation of phosphoethanolamine to the O-6 of l-glycero-d-mano-heptose II. The eptC gene is found in all the P. mirabilis strains analyzed in this study. Putative eptC homologues were found for only two additional genera of the Enterobacteriaceae family, Photobacterium and Providencia. The data obtained in this work supports the role of the eptC (PMI3104) product in the transfer of PEtN to the O-6 of l,d-HepII in P. mirabilis strains.
Selected Activities of Citrus Maxima Merr. Fruits on Human Endothelial Cells: Enhancing Cell Migration and Delaying Cellular Aging
Authors: Buachan Paiwan , Chularojmontri Linda , Wattanapitayakul Suvara
Published: April 2014

Endothelial injury and damage as well as accumulated reactive oxygen species (ROS) in aging play a significant role in the development of cardiovascular disease (CVD). Recent studies show an association of high citrus fruit intake with a lower risk of CVD and stroke but the mechanisms involved are not fully understood. This study investigated the effects of pummelo (Citrus maxima Merr. var. Tubtim Siam, CM) fruit extract on human umbilical vein endothelial cell (HUVECs) migration and aging. The freeze-dried powder of fruit extract was characterized for antioxidant capacity (FRAP assay) and certain natural antioxidants, including ascorbic acid, gallic acid, hesperidin, and naringin (HPLC). Short-term (48 h) co-cultivation of HUVECs with CM enhanced cell migration as evaluated by a scratch wound assay and Boyden chamber assay. A long-term treatment with CM for 35 days significantly increased HUVEC proliferation capability as indicated by population doubling level (PDL). CM also delayed the onset of aging phenotype shown by senescence-associated β-galactosidase (SA-β-gal) staining. Furthermore, CM was able to attenuate increased ROS levels in aged cells when determined by 2′,7′-dichlorodihydrofluorescein diacetate (DCDHF) while eNOS mRNA expression was increased but the eNOS protein level was not changed. Thus, further in vivo and clinical studies are warranted to support the use of pummelo as a functional fruit for endothelial health and CVD risk reduction.
Intake of Tibetan Hull-Less Barley is Associated with a Reduced Risk of Metabolic Related Syndrome in Rats Fed High-Fat-Sucrose Diets
Authors: Gong Lingxiao , Gong Lingyun , Zhang Ying
Published: April 2014

The objective of this study was to assess the effects of whole grain Tibetan hull-less barley on metabolic related syndrome induced by high-fat-sucrose diets in rats. The diets were designed to reflect the dietary patterns of Chinese individuals (>30% energy fat) with refined wheat flour (HFS-W) or Tibetan hull-less barley (HFS-THB) as the main carbohydrate sources. Rats fed HFS-W had increased body weight, abdominal fat deposition, liver weight, liver fat deposition, triglyceride (TG), fasting blood glucose (FBG), serum fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR) scores, and decreased low-density lipoprotein cholesterol (LDL-C) levels compared to rats fed a basal diet (BD). However, rats fed HFS-THB had reduced body weight gain, dyslipidemia, and insulin resistance. These findings indicate that whole Tibetan hull-less barley is a functional food that can reduce the prevalence of metabolic related syndrome induced by high-fat-sucrose diets.
Caffeine Intake May Modulate Inflammation Markers in Trained Rats
Authors: Barcelos Rômulo , Souza Mauren , Amaral Guilherme , Stefanello Silvio , Bresciani Guilherme , Fighera Michele , Soares Félix , De Vargas Barbosa Nilda
Published: April 2014

Caffeine is presented in many commercial products and has been proven to induce ergogenic effects in exercise, mainly related to redox status homeostasis, inflammation and oxidative stress-related adaptation mechanisms. However, most studies have mainly focused on muscle adaptations, and the role of caffeine in different tissues during exercise training has not been fully described. The aim of this study was therefore, to analyze the effects of chronic caffeine intake and exercise training on liver mitochondria functioning and plasma inflammation markers. Rats were divided into control, control/caffeine, exercise, and exercise/caffeine groups. Exercise groups underwent four weeks of swimming training and caffeine groups were supplemented with 6 mg/kg/day. Liver mitochondrial swelling and complex I activity, and plasma myeloperoxidase (MPO) and acetylcholinesterase (AChE) activities were measured. An anti-inflammatory effect of exercise was evidenced by reduced plasma MPO activity. Additionally, caffeine intake alone and combined with exercise decreased the plasma AChE and MPO activities. The per se anti-inflammatory effect of caffeine intake should be highlighted considering its widespread use as an ergogenic aid. Therefore, caffeine seems to interfere on exercise-induced adaptations and could also be used in different exercise-related health treatments.
Calcul économique et incertitude socio-politique : une procédure d’évaluation des projets publics
Authors: Kast Robert , Luchini Stéphane
Published: April 2014

Public Contract Bidding : Fixed-Price Contracts Amended by Change Orders or Incentive Contracts ?

French procurement contracts are usually awarded by fixed-price contracts. However, fixed prices can be raised by change orders that occur after the contract is signed. The authors develop a model of this procedure that gives an explanation for low-ball bidding strategies and cost overruns. Then the authors show that this procedure can yield an expected price lower than the optimal linear incentive contract of McAfee and McMillan (1986).
Modification of the Amino Terminus of a Class II Epitope Confers Resistance to Degradation by CD13 on Dendritic Cells and Enhances Presentation to T Cells
Authors: Dong Xin , An Bing , Salvucci Kierstead Lisa , Storkus Walter J. , Amoscato Andrew A. , Salter Russell D.
Published: April 2014

Dendritic cells and human B cell lines were compared for ability to present synthetic peptides corresponding to residues 145–159 and 188–203 of human Ig κ-chains to peptide-specific mouse T cell hybridomas restricted by HLA-DR4Dw4. B cell lines presented both peptides, but dendritic cells could only efficiently present the latter epitope. In this paper, we show that dendritic cells degrade the 145–159 peptide, removing four residues from the amino terminus. Binding of the peptide to the class II restriction element is not required for this process. The degradation product is resistant to further cleavage, accumulates in the culture supernatant, and does not bind to HLA-DR4Dw4 or stimulate T cell reactivity. Cleavage can be blocked with bestatin, but not with other protease inhibitors tested, or by a mAb directed against aminopeptidase N (CD13). Addition of an acetyl group to the amino terminus of peptide 145–159 also blocks degradation, and allows dendritic cells to present the peptide to specific T cells with greatly increased efficiency. These results demonstrate that CD13 on dendritic cells is able to selectively and efficiently degrade exogenously provided peptide Ags, in a process that can be blocked by addition of an acetyl group to the amino terminus of the peptide. Modification of the amino terminus of peptide epitopes susceptible to degradation may prove to be useful as a general strategy for enhancing their immunogenicity.
Cutting Edge: Heat Shock Protein (HSP) 60 Activates the Innate Immune Response: CD14 Is an Essential Receptor for HSP60 Activation of Mononuclear Cells
Authors: Kol Amir , Lichtman Andrew H. , Finberg Robert W. , Libby Peter , Kurt-Jones Evelyn A.
Published: April 2014

Heat shock proteins (HSP), highly conserved across species, are generally viewed as intracellular proteins thought to serve protective functions against infection and cellular stress. Recently, we have reported the surprising finding that human and chlamydial HSP60, both present in human atheroma, can activate vascular cells and macrophages. However, the transmembrane signaling pathways by which extracellular HSP60 may activate cells remains unclear. CD14, the monocyte receptor for LPS, binds numerous microbial products and can mediate activation of monocytes/macrophages and endothelial cells, thus promoting the innate immune response. We show here that human HSP60 activates human PBMC and monocyte-derived macrophages through CD14 signaling and p38 mitogen-activated protein kinase, sharing this pathway with bacterial LPS. These findings provide further insight into the molecular mechanisms by which extracellular HSP may participate in atherosclerosis and other inflammatory disorders by activating the innate immune system.
A Critical Role for B7/CD28 Costimulation in Experimental Autoimmune Encephalomyelitis: A Comparative Study Using Costimulatory Molecule-Deficient Mice and Monoclonal Antibody Blockade
Authors: Girvin Ann M. , Dal Canto Mauro C. , Rhee Lesley , Salomon Benoît , Sharpe Arlene , Bluestone Jeffrey A. , Miller Stephen D.
Published: April 2014

The B7/CD28 pathway provides critical costimulatory signals required for complete T cell activation and has served as a potential target for immunotherapeutic strategies designed to regulate autoimmune diseases. This study was designed to examine the roles of CD28 and its individual ligands, B7-1 and B7-2, in experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the CNS. EAE induction in CD28- or B7-deficient nonobese diabetic (NOD) mice was compared with the effects of B7/CD28 blockade using Abs in wild-type NOD mice. Disease severity was significantly reduced in CD28-deficient as well as anti-B7-1/B7-2-treated NOD mice. B7-2 appeared to play the more dominant role as there was a moderate decrease in disease incidence and severity in B7-2-deficient animals. EAE resistance was not due to the lack of effective priming of the myelin peptide-specific T cells in vivo. T cells isolated from CD28-deficient animals produced equivalent amounts of IFN-γ and TNF-α in response to the immunogen, proteolipid protein 56–70. In fact, IFN-γ and TNF-α production by Ag-specific T cells was enhanced in both the B7-1 and B7-2-deficient NOD mice. In contrast, peptide-specific delayed-type hypersensitivity responses in these animals were significantly decreased, suggesting a critical role for CD28 costimulation in in vivo trafficking and systemic immunity. Collectively, these results support a critical role for CD28 costimulation in EAE induction.
Dendritic Cells Genetically Engineered to Express Fas Ligand Induce Donor-Specific Hyporesponsiveness and Prolong Allograft Survival
Authors: Min Wei-Ping , Gorczynski Reginald , Huang Xu-Yan , Kushida Michelle , Kim Peter , Obataki Masayuki , Lei Ji , Suri Rakesh M. , Cattral Mark S.
Published: April 2014

Polarization of an immune response toward tolerance or immunity is dictated by the interactions between T cells and dendritic cells (DC), which in turn are modulated by the expression of distinct cell surface molecules, and the cytokine milieu in which these interactions are taking place. Genetic modification of DC with genes coding for specific immunoregulatory cell surface molecules and cytokines offers the potential of inhibiting immune responses by selectively targeting Ag-specific T cells. In this study, the immunomodulatory effects of transfecting murine bone marrow-derived DC with Fas ligand (FasL) were investigated. In this study, we show that FasL transfection of DC markedly augmented their capacity to induce apoptosis of Fas+ cells. FasL-transfected DC inhibited allogeneic MLR in vitro, and induced hyporesponsiveness to alloantigen in vivo. The induction of hyporesponsiveness was Ag specific and was dependent on the interaction between FasL on DC and Fas on T cells. Finally, we show that transfusion of FasL-DC significantly prolonged the survival of fully MHC-mismatched vascularized cardiac allografts. Our findings suggest that DC transduced with FasL may facilitate the development of Ag-specific unresponsiveness for the prevention of organ rejection. Moreover, they highlight the potential of genetically engineering DC to express other genes that affect immune responses.
Bacterial Proteins Can Be Processed by Macrophages in a Transporter Associated with Antigen Processing-Independent, Cysteine Protease-Dependent Manner for Presentation by MHC Class I Molecules
Authors: Campbell Daniel J. , Serwold Thomas , Shastri Nilabh
Published: April 2014

MHC class I molecules present peptides derived primarily from endogenously synthesized proteins on the cell surface as ligands for CD8+ T cells. However, CD8+ T cell responses to extracellular bacteria, virus-infected, or tumor cells can also be elicited because certain professional APC can generate peptide/MHC class I (MHC-I) complexes from exogenous sources. Whether the peptide/MHC-I complexes are generated because the exogenous proteins enter the classical cytosolic, TAP-dependent MHC-I processing pathway or an alternate pathway is controversial. Here we analyze the generation of peptide/MHC-I complexes from recombinant Escherichia coli as an exogenous Ag source that could be delivered to the phagosomes or directly into the cytosol. We show that peritoneal and bone marrow macrophages generate peptide/MHC-I complexes by the classical as well as an alternate, but relatively less efficient, TAP-independent pathway. Using a novel method to detect proteolytic intermediates we show that the generation of the optimal MHC-I binding peptide in the alternate pathway requires cysteine as well as other protease(s). This alternate TAP-independent pathway also operates in vivo and provides a potential mechanism for eliciting CD8+ T cell responses to exogenous Ags.
Cutting Edge: Lack of Peripheral B Cells and Severe Agammaglobulinemia in Mice Simultaneously Lacking Bruton’s Tyrosine Kinase and the B Cell-Specific Transcriptional Coactivator OBF-1
Authors: Schubart Daniel B. , Rolink Antonius , Schubart Karin , Matthias Patrick
Published: April 2014

OBF-1 is a B cell-restricted transcriptional coactivator that is recruited to octamer-containing promoters by interacting with the POU domain of Oct-1 or Oct-2. We have shown earlier that mice lacking OBF-1 were dramatically impaired in their ability to mount humoral immune responses and did not develop germinal centers in the spleen; however, they had a largely normal B cell development in the bone marrow. In this study, we demonstrate that OBF-1-deficient mice also have an early defect in B cell development and show that OBF-1−/− immature B cells are greatly impaired at the transition from the bone marrow to the spleen. In addition, when the OBF-1 mutation is combined to a mutation in the gene encoding Bruton’s tyrosine kinase, a striking phenotype is observed. These double-deficient animals lack peripheral B cells and have virtually no serum Igs, thus closely resembling human X chromosome-linked agammaglobulinemia.
Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas
Authors: Nugent C. Thomas , Morgan David J. , Biggs Judith A. , Ko Alice , Pilip Ingrid M. , Pamer Eric G. , Sherman Linda A.
Published: April 2014

As a result of expression of the influenza hemagglutinin (HA) in the pancreatic islets, the repertoire of HA-specific CD8+ T lymphocytes in InsHA transgenic mice (D2 mice expressing the HA transgene under control of the rat insulin promoter) is comprised of cells that are less responsive to cognate Ag than are HA-specific CD8+ T lymphocytes from conventional mice. Previous studies of tolerance induction involving TCR transgenic T lymphocytes suggested that a variety of different mechanisms can reduce avidity for Ag, including altered cell surface expression of molecules involved in Ag recognition and a deficiency in signaling through the TCR complex. To determine which, if any, of these mechanisms pertain to CD8+ T lymphocytes within a conventional repertoire, HA-specific CD8+ T lymphocytes from B10.D2 mice and B10.D2 InsHA transgenic mice were compared with respect to expression of cell surface molecules, TCR gene utilization, binding of tetrameric KdHA complexes, lytic mechanisms, and diabetogenic potential. No evidence was found for reduced expression of TCR or CD8 by InsHA-derived CTL, nor was there evidence for a defect in triggering lytic activity. However, avidity differences between CD8+ clones correlated with their ability to bind KdHA tetramers. These results argue that most of the KdHA-specific T lymphocytes in InsHA mice are not intrinsically different from KdHA-specific T lymphocytes isolated from conventional animals. They simply express TCRs that are less avid in their binding to KdHA.
Surface Expression of the IFN-γR2 Chain Is Regulated by Intracellular Trafficking in Human T Lymphocytes
Authors: Rigamonti Laura , Ariotti Silvia , Losana Giuliana , Gradini Roberto , Russo Matteo A. , Jouanguy Emmanuelle , Casanova Jean-Laurent , Forni Guido , Novelli Francesco
Published: April 2014

The surface and cytoplasmic expressions of the transducing chain (IFN-γR2) of the heterodimeric IFN-γ receptor on human T lymphocytes have been investigated. We show that its surface expression is low, whereas high cytoplasmic levels are found in both resting and PHA-activated T lymphocytes. This low expression does not prevent activated T cells from responding to IFN-γ, because it induces IFN-regulatory factor 1 expression. Low surface IFN-γR2 expression appears to be due to recycling between cytoplasmic stores and the cell surface, which does not depend on signals mediated by endogenous IFN-γ, because IFN-γR2 surface expression is low, and its internalization is equally observed in patients with inherited IFN-γR1 gene deficiency and in healthy donors. Moreover, IFN-γR2 internalization in T lymphoblasts from healthy donors was not affected by the presence of anti-IFN-γ-neutralizing or anti-IFN-γR1-blocking mAb. In conclusion, these data illustrate a new mechanism whereby human T cells limit the surface expression of IFN-γR2 in a ligand-independent manner.
Activated and Memory CD8+ T Cells Can Be Distinguished by Their Cytokine Profiles and Phenotypic Markers
Authors: Slifka Mark K. , Whitton J. Lindsay
Published: April 2014

Dissecting the mechanisms of T cell-mediated immunity requires the identification of functional characteristics and surface markers that distinguish between activated and memory T lymphocytes. In this study, we compared the rates of cytokine production by virus-specific primary and memory CD8+ T cells directly ex vivo. Ag-specific IFN-γ and TNF-α production by both primary and long-term memory T cells was observed in ≤60 min after peptide stimulation. Although the on-rate kinetics of cytokine production were nearly identical, activated T cells produced more IFN-γ, but less TNF-α, than memory T cells. Ag-specific cytokine synthesis was not a constitutive process and terminated immediately following disruption of contact with peptide-coated cells, demonstrating that continuous antigenic stimulation was required by both T cell populations to maintain steady-state cytokine production. Upon re-exposure to Ag, activated T cells resumed cytokine production whereas only a subpopulation of memory T cells reinitiated cytokine synthesis. Analysis of cytokine profiles and levels of CD8, LFA-1, and CTLA-4 together revealed a pattern of expression that clearly distinguished in vivo-activated T cells from memory T cells. Surprisingly, CTLA-4 expression was highest at the early stages of the immune response but fell to background levels soon after viral clearance. This study is the first to show that memory T cells have the same Ag-specific on/off regulation of cytokine production as activated T cells and demonstrates that memory T cells can be clearly discriminated from activated T cells directly ex vivo by their cytokine profiles and the differential expression of three well-characterized T cell markers.
Vaccination with Heat-KilledListeriaas Adjuvant Reverses Established Allergen-Induced Airway Hyperreactivity and Inflammation: Role of CD8+ T Cells and IL-18
Authors: Hansen Gesine , Yeung V. Peter , Berry Gerald , Umetsu Dale T. , DeKruyff Rosemarie H.
Published: April 2014

Asthma is a respiratory disorder characterized by airway hyperreactivity (AHR) and inflammation and is associated with high serum IgE and overproduction of IL-4, IL-5, and IL-13 by allergen-specific Th2 cells. Our previous studies demonstrated that heat-killed Listeria monocytogenes (HKL) as an adjuvant in immunotherapy successfully reversed ongoing Ag-specific Th2-dominated responses toward Th1-dominated responses, but it was unclear if such immune modulation could reverse ongoing, established disease in target organs such as the lung. In this paper we show that a single dose of Ag plus HKL as adjuvant significantly reduced AHR in a murine model for asthma and reversed established AHR when given late after allergen sensitization. HKL as adjuvant also dramatically inhibited airway inflammation, eosinophilia, and mucus production, significantly reduced Ag-specific IgE and IL-4 production, and dramatically increased Ag-specific IFN-γ synthesis. The inhibitory effect of HKL on AHR depended on the presence of IL-12 and CD8+ T cells and was associated with an increase of IL-18 mRNA expression. Thus, our results demonstrate that HKL as an adjuvant for immunotherapy mediates immune deviation from a pathological Th2-dominated response toward a protective immune response in peripheral lymphoid tissues and in the lungs and may be clinically effective in the treatment of patients with established asthma and allergic disease.