bluuebunny/crossref_metadata_2025 huggingface dataset:
Experiences in Usability Evaluation of Educational Programming Tools
Authors: Velázquez-Iturbide J. Ángel , Pérez-Carrasco Antonio , Debdi Ouafae
Published: September 2012

This chapter advocates for an approach to constructing educational tools that consists in designing small systems aimed at achieving clear educational goals and evaluating them in actual teaching situations. The authors addressed this approach with a number of small systems. In this chapter, they describe their experience in the development, use, and evaluation of two educational systems: SRec and GreedEx. The former is a highly interactive program animation system of recursion, and the latter is an interactive assistant aimed at learning the role of selection functions in greedy algorithms by means of experimentation. The evaluations allowed the authors to identify faults and weaknesses of the systems, and these results were used to enhance the systems. Moreover, their approach has yielded very high values with respect to effectiveness and student satisfaction.
User’s Experience with a 3D Educational Mobile Game to Support Spatial Instruction
Authors: Martin-Dorta Norena , Sanchez-Berriel Isabel , Saorin Jose Luis , Contero Manuel
Published: September 2012

Spatial abilities are critical skills in scientific and technical fields. In recent studies, the role of computer games, particularly those with 3-D simulations, have been examined for their impact on the development of spatial skills. The work presented in this chapter describes the design and user evaluation of a 3D construction mobile game called iCube. A trial version was brought out and evaluated by twenty-two students. Users pointed out that the game is useful for improvement of spatial ability and is fun. However, some difficulties arose with use of the tactile screen, as fingerprints caused problems while interacting with the game’s 3D environment. The results revealed that it is necessary to have this item in mind during the game’s design, where screen action is continuous.
Benefits of Virtual Worlds in Educational Environments
Authors: Galiano Vicente , Herranz Victoria
Published: September 2012

In this chapter, the authors describe the project of a virtual world that they developed in their university and with their students. In this work, they joined concepts like social networks and virtual reality, creating a virtual model of the University Miguel Hernandez (UMH), where students are able to walk around the campus, inside the buildings, chat with other students, and moreover, use videoconferencing rooms where students talk and see other students in the same virtual world. The authors describe this project, called UMHvirtual (available in http://virtual.umh.es), which has been supervised by the authors, implemented by a group of students, and focused on all the university students.
Collaborative Production, the Knowledge Commons and the Application of Open Content Licenses
Authors: Pang Natalie
Published: September 2012

In recent years impacts of information and communication technologies, market enclosures, and the opposing struggle to retain community and public goods have had significant impacts on the social interactions of communities. This chapter examines communities in the context of the knowledge commons – a space by which “a particular type of freedom” (Benkler, 2004) can be practised. It also provides an appropriate lexicon to the examination and discourse of communities and the ways they work. As Castells (2003) notes, self-knowledge “is always a construction no matter how much it feels like a discovery” –this construction is enabled when people work or associate themselves with each other. In particular, the chapter is concerned about the structure of open content licenses operating within such domains. The chapter first explores the concept of the knowledge commons to understand the types of intellectual property that are distinctive to communities (public, communal, and private). Thereafter, licenses as a structure are examined as they may apply within such contexts. A significant influence on the discussion is the contemporary media environment that communities operate in today, resulting in the breaking down of boundaries, the blurring of distinctions between an original and a copy, and shifting the nature of production in communities. These debates lead to a case for open content licenses as an appropriate structural mechanism for communities.
Improving Internal Supply Chain Collaboration by Increasing Information-Processing Capacity
Authors: Feger Ana L. Rosado
Published: September 2012

This study examines the role of enterprise information systems in fostering collaboration between the Purchasing, Production, and Outbound Logistics functions of manufacturing facilities. These forms of integrative information technology are considered key facilitators of supply chain management. The research model embeds these systems within a broader model of facilitators of interfunctional integration. The model is tested by path analysis, using a survey sample of 120 manufacturing facilities located in the United States. The results suggest that integrative information technology has a significant effect on collaboration, and that the level of demand uncertainty moderates the effect on collaboration.
A Classification Framework of Critical Success Factors for ERP Systems Implementation
Authors: Nour Mohamed A. , Mouakket Samar
Published: September 2012

Although organizations can gain many benefits from successful implementation of an enterprise resource planning (ERP) system, there are high failure rates in ERP implementation projects. Therefore, a better understanding of ERP implementation success is a critical. One of the best known approaches used to define and measure ERP implementation success has been the critical success factors (CSF) approach. In this study, the authors investigate the current literature of critical success factors (CSFs) of ERP systems implementation and propose a new classification framework, categorized according to six proposed fundamental stakeholders. The authors then map those critical success factors to three different stages of an ERP project lifecycle. In addition, they identify several roles that each stakeholder may play during the ERP systems project lifecycle. The proposed classification framework provides organizations with a classification tool to help them identify the CSFs and those stakeholders who are most likely to have an impact on the implementation of the ERP system, which will help organizations to better plan for the implementation of their ERP systems.
Strategic Management of Network Resources
Authors: Antero Michelle , Riis Philip Holst
Published: September 2012

This paper applies the resource-based view (RBV) theory to a case study aimed at identifying the complementary resources among partners in the ERPCorp ecosystem of development and implementation of Enterprise Resource Planning (ERP) for small and medium enterprises (SMEs) in Denmark. The paper analyzes these resources in terms of being valuable, rare, inimitable, immobile, and non-substitutable in the ERP solutions market. The study found four key complementary resources that contribute to competitive advantage, namely: (1) ERP core product; (2) horizontal add-ons; (3) vertical add-ons; and (4) customer specific add-ons. The paper examines the potential impact of an ERP vendor’s business development strategy that includes changing the ERP solution from a horizontal to a vertical focus, and increasing the partner certification requirements to be part of the ecosystem. The evidence suggests that the strategy, if implemented successfully, maintains competitive advantage for the ERPCorp ecosystem through effectively combining resources and leveraging lock-in and network effects.
Ontology-Based Knowledge Management for Enterprise Systems
Authors: Ahmad Mohammad Nazir , Zakaria Nor Hidayati , Sedera Darshana
Published: September 2012

Companies face the challenges of expanding their markets, improving products, services and processes, and exploiting intellectual capital in a dynamic network. Therefore, more companies are turning to an Enterprise System (ES). Knowledge management (KM) has also received considerable attention and is continuously gaining the interest of industry, enterprises, and academia. For ES, KM can provide support across the entire lifecycle, from selection and implementation to use. In addition, it is also recognised that an ontology is an appropriate methodology to accomplish a common consensus of communication, as well as to support a diversity of KM activities, such as knowledge repository, retrieval, sharing, and dissemination. This paper examines the role of ontology-based KM for ES (OKES) and investigates the possible integration of ontology-based KM and ES. The authors develop a taxonomy as a framework for understanding OKES research. In order to achieve the objective of this study, a systematic review of existing research was conducted. Based on a theoretical framework of the ES lifecycle, KM, KM for ES, ontology, and ontology-based KM, guided by the framework of study, a taxonomy for OKES is established.
Determination of the Number of Clusters in a Data Set
Authors: Boone Derrick S.
Published: September 2012

The accuracy of “stopping rules” for determining the number of clusters in a data set is examined as a function of the underlying clustering algorithm being used. Using a Monte Carlo study, various stopping rules, used in conjunction with six clustering algorithms, are compared to determine which rule/algorithm combinations best recover the true number of clusters. The rules and algorithms are tested using disparately sized, artificially generated data sets that contained multiple numbers and levels of clusters, variables, noise, outliers, and elongated and unequally sized clusters. The results indicate that stopping rule accuracy depends on the underlying clustering algorithm being used. The cubic clustering criterion (CCC), when used in conjunction with mixture models or Ward’s method, recovers the true number of clusters more accurately than other rules and algorithms. However, the CCC was more likely than other stopping rules to report more clusters than are actually present. Implications are discussed.
Towards Practical ABox Abduction in Large Description Logic Ontologies
Authors: Du Jianfeng , Qi Guilin , Shen Yi-Dong , Pan Jeff Z.
Published: September 2012

ABox abduction is an important reasoning facility in Description Logics (DLs). It finds all minimal sets of ABox axioms, called abductive solutions, which should be added to a background ontology to enforce entailment of an observation which is a specified set of ABox axioms. However, ABox abduction is far from practical by now because there lack feasible methods working in finite time for expressive DLs. To pave a way to practical ABox abduction, this paper proposes a new problem for ABox abduction and a new method for computing abductive solutions accordingly. The proposed problem guarantees finite number of abductive solutions. The proposed method works in finite time for a very expressive DL, , which underpins the W3C standard language OWL 2, and guarantees soundness and conditional completeness of computed results. Experimental results on benchmark ontologies show that the method is feasible and can scale to large ABoxes.
Role of Macrophage Migration Inhibitory Factor in the Regulatory T Cell Response of Tumor-Bearing Mice
Authors: Choi Susanna , Kim Hang-Rae , Leng Lin , Kang Insoo , Jorgensen William L. , Cho Chul-Soo , Bucala Richard , Kim Wan-Uk
Published: September 2012

Macrophage migration inhibitory factor (MIF) is involved in tumorigenesis by facilitating tumor proliferation and evasion of apoptosis; however, its role in tumor immunity is unclear. In this study, we investigated the effect of MIF on the progression of the syngenic, CT26 colon carcinoma and the generation of tumor regulatory T cells (Tregs). The results showed that the tumor growth rate was significantly lower in MIF knockout (MIF−/−) mice than in wild-type (MIF+/+) mice. Flow cytometric analysis of both spleen and tumor cells revealed that MIF−/− mice had significantly lower levels of tumor-associated CD4+Tregs than MIF+/+ mice. The splenic cells of MIF−/− mice also showed a decrease in CD8+Tregs, which was accompanied by an increase in CD8-induced tumor cytotoxicity. Interestingly, the inducible Treg response in spleen cells to anti-CD3/CD28 plus IL-2 plus TGF-β was greater in MIF−/− mice than in MIF+/+ mice. Spleen cells of MIF−/− mice, stimulated with anti-CD3/CD28, produced lower levels of IL-2, but not TGF-β, than those of MIF+/+ mice, which was recovered by the addition of recombinant MIF. Conversely, a neutralizing anti-MIF Ab blocked anti-CD3–induced IL-2 production by splenocytes of MIF+/+ mice and suppressed the inducible Treg generation. Moreover, the administration of IL-2 into tumor-bearing MIF−/− mice restored the generation of Tregs and tumor growth. Taken together, our data suggest that MIF promotes tumor growth by increasing Treg generation through the modulation of IL-2 production. Thus, anti-MIF treatment might be useful in enhancing the adaptive immune response to colon cancers.
Regulation of Inflammatory Response by 3-Methyladenine Involves the Coordinative Actions on Akt and Glycogen Synthase Kinase 3β Rather than Autophagy
Authors: Lin Yi-Chieh , Kuo Hsuan-Cheng , Wang Jang-Shiun , Lin Wan-Wan
Published: September 2012

3-Methyladenine (3-MA) is one of the most commonly used inhibitors in autophagy research today. However, rather than inhibiting class III PI3K that is involved in autophagy suppression, 3-MA might also interfere with class I PI3K and consequently augment autophagy flux. In this study, we aim to get a thorough understanding on the action mechanisms of 3-MA in TLR4-mediated inflammatory responses in RAW264.7 macrophages and, moreover, to decipher the action of 3-MA in modulation of autophagy. We found that 3-MA could enhance LPS-induced NF-κB activation and production of TNF-α, inducible NO synthase (iNOS), cyclooxygenase-2, IL-1β, and IL-12. In contrast, 3-MA suppressed LPS-induced IFN-β production and STAT signaling. Studies revealed that 3-MA can, through inhibition of Akt as a result of class I PI3K interference, positively regulate p38, JNK, and p65, but negatively regulate TANK-binding kinase 1 and IFN regulatory factor 3 mediated by TLR4. As glycogen synthase kinase 3β (GSK3β) is an important Akt substrate, we further explored its involvement in the actions of 3-MA. 3-MA was found to enhance LPS-induced NF-κB activation, iNOS, and pro–IL-1β expression, and these actions were reversed by either GSK3β inhibitors or small interfering GSK3β. Lastly, we demonstrated that 3-MA acts as an autophagy inducer in RAW264.7 macrophages, but the stimulating effects on NF-κB activation and iNOS and cyclooxygenase-2 expression were not affected in LPS-stimulated macrophages with small interfering autophagy protein-5 treatment. These results not only shed new light on the action mechanisms of 3-MA to differentially regulate inflammatory outcomes derived from TLR4-mediated MyD88 and Toll/IL-1R domain-containing adapter inducing IFN-β pathways, but also highlight the necessity to check autophagy status upon taking 3-MA as a general autophagy inhibitor.
IL-10–Producing Regulatory B Cells in the Pathogenesis of Chronic Hepatitis B Virus Infection
Authors: Das Abhishek , Ellis Gidon , Pallant Celeste , Lopes A. Ross , Khanna Pooja , Peppa Dimitra , Chen Antony , Blair Paul , Dusheiko Geoffrey , Gill Upkar , Kennedy Patrick T. , Brunetto Maurizia , Lampertico Pietro , Mauri Claudia , Maini Mala K.
Published: September 2012

A regulatory subset of B cells has been found to modulate immune responses in autoimmunity, infection, and cancer, but it has not been investigated in the setting of human persistent viral infection. IL-10 is elevated in patients with chronic hepatitis B virus infection (CHB), but its cellular sources and impact on antiviral T cells have not been addressed. We investigated the role of IL-10 and regulatory B cells in the pathogenesis of CHB. Serum IL-10 levels were studied longitudinally in patients with CHB undergoing spontaneous disease flares. There was a close temporal correlation between IL-10 levels and fluctuations in viral load or liver inflammation. Blockade of IL-10 in vitro rescued polyfunctional virus-specific CD8 T cell responses. To investigate the potential contribution of regulatory B cells, their frequency was measured directly ex vivo and after exposure to stimuli relevant to hepatitis B virus (HBV) (CpG or HBV Ags). IL-10–producing B cells were enriched in patients, and their frequency correlated temporally with hepatic flares, both after stimulation and directly ex vivo. Phenotypically, these cells were predominantly immature (CD19+CD24hiCD38hi) ex vivo; sorted CD19+CD24hiCD38hi cells suppressed HBV-specific CD8 T cell responses in an IL-10–dependent manner. In summary, these data reveal a novel IL-10–producing subset of B cells able to regulate T cell immunity in CHB.
Extensive Diversification of IgD-, IgY-, and Truncated IgY(ΔFc)-Encoding Genes in the Red-Eared Turtle (Trachemys scripta elegans)
Authors: Li Lingxiao , Wang Tao , Sun Yi , Cheng Gang , Yang Hui , Wei Zhiguo , Wang Ping , Hu Xiaoxiang , Ren Liming , Meng Qingyong , Zhang Ran , Guo Ying , Hammarström Lennart , Li Ning , Zhao Yaofeng
Published: September 2012

IgY(ΔFc), containing only CH1 and CH2 domains, is expressed in the serum of some birds and reptiles, such as ducks and turtles. The duck IgY(ΔFc) is produced by the same υ gene that expresses the intact IgY form (CH1–4) using different transcriptional termination sites. In this study, we show that intact IgY and IgY(ΔFc) are encoded by distinct genes in the red-eared turtle (Trachemys scripta elegans). At least eight IgY and five IgY(ΔFc) transcripts were found in a single turtle. Together with Southern blotting, our data suggest that multiple genes encoding both IgY forms are present in the turtle genome. Both of the IgY forms were detected in the serum using rabbit polyclonal Abs. In addition, we show that multiple copies of the turtle δ gene are present in the genome and that alternative splicing is extensively involved in the generation of both the secretory and membrane-bound forms of the IgD H chain transcripts. Although a single μ gene was identified, the α gene was not identified in this species.
IFN-α and Lipopolysaccharide Upregulate APOBEC3 mRNA through Different Signaling Pathways
Authors: Mehta Harshini V. , Jones Philip H. , Weiss Jerrold P. , Okeoma Chioma M.
Published: September 2012

APOBEC3 (A3) proteins are virus-restriction factors that provide intrinsic immunity against infections by viruses like HIV-1 and mouse mammary tumor virus. A3 proteins are inducible by inflammatory stimuli, such as LPS and IFN-α, via mechanisms that are not fully defined. Using genetic and pharmacological studies on C57BL/6 mice and cells, we show that IFN-α and LPS induce A3 via different pathways, independently of each other. IFN-α positively regulates mouse APOBEC3 (mA3) mRNA expression through IFN-αR/PKC/STAT1 and negatively regulates mA3 mRNA expression via IFN-αR/MAPKs–signaling pathways. Interestingly, LPS shows some variation in its regulatory behavior. Although LPS-mediated positive regulation of mA3 mRNA occurs through TLR4/TRIF/IRF3/PKC, it negatively modulates mA3 mRNA via TLR4/MyD88/MAPK-signaling pathways. Additional studies on human peripheral blood mononuclear cells reveal that PKC differentially regulates IFN-α and LPS induction of human A3A, A3F, and A3G mRNA expression. In summary, we identified important signaling targets downstream of IFN-αR and TLR4 that mediate A3 mRNA induction by both LPS and IFN-α. Our results provide new insights into the signaling targets that could be manipulated to enhance the intracellular store of A3 and potentially enhance A3 antiviral function in the host.
MicroRNAs Control the Maintenance of Thymic Epithelia and Their Competence for T Lineage Commitment and Thymocyte Selection
Authors: Zuklys Saulius , Mayer Carlos E. , Zhanybekova Saule , Stefanski Heather E. , Nusspaumer Gretel , Gill Jason , Barthlott Thomas , Chappaz Stephane , Nitta Takeshi , Dooley James , Nogales-Cadenas Ruben , Takahama Yousuke , Finke Daniela , Liston Adrian , Blazar Bruce R. , Pascual-Montano Alberto , Holländer Georg A.
Published: September 2012

Thymic epithelial cells provide unique cues for the lifelong selection and differentiation of a repertoire of functionally diverse T cells. Rendered microRNA (miRNA) deficient, these stromal cells in the mouse lose their capacity to instruct the commitment of hematopoietic precursors to a T cell fate, to effect thymocyte positive selection, and to achieve promiscuous gene expression required for central tolerance induction. Over time, the microenvironment created by miRNA-deficient thymic epithelia assumes the cellular composition and structure of peripheral lymphoid tissue, where thympoiesis fails to be supported. These findings emphasize a global role for miRNA in the maintenance and function of the thymic epithelial cell scaffold and establish a novel mechanism how these cells control peripheral tissue Ag expression to prompt central immunological tolerance.
Dendritic Cell-Specific Disruption of TGF-β Receptor II Leads to Altered Regulatory T Cell Phenotype and Spontaneous Multiorgan Autoimmunity
Authors: Ramalingam Rajalakshmy , Larmonier Claire B. , Thurston Robert D. , Midura-Kiela Monica T. , Zheng Song Guo , Ghishan Fayez K. , Kiela Pawel R.
Published: September 2012

In vitro data and transgenic mouse models suggest a role for TGF-β signaling in dendritic cells (DCs) to prevent autoimmunity primarily through maintenance of DCs in their immature and tolerogenic state characterized by low expression of MHC class II (MHCII) and costimulatory molecules and increased expression of IDO, among others. To test whether a complete lack of TGF-β signaling in DCs predisposes mice to spontaneous autoimmunity and to verify the mechanisms implicated previously in vitro, we generated conditional knockout (KO) mice with Cre-mediated DC-specific deletion of Tgfbr2 (DC-Tgfbr2 KO). DC-Tgfbr2 KO mice die before 15 wk of age with multiorgan autoimmune inflammation and spontaneous activation of T and B cells. Interestingly, there were no significant differences in the expression of MHCII, costimulatory molecules, or IDO in secondary lymphoid organ DCs, although Tgfbr2-deficient DCs were more proinflammatory in vitro and in vivo. DC-Tgfbr2 KO showed attenuated Foxp3 expression in regulatory T cells (Tregs) and abnormal expansion of CD25−Foxp3+ Tregs in vivo. Tgfbr2-deficient DCs secreted elevated levels of IFN-γ and were not capable of directing Ag-specific Treg conversion unless in the presence of anti–IFN-γ blocking Ab. Adoptive transfer of induced Tregs into DC-Tgfbr2 KO mice partially rescued the phenotype. Therefore, in vivo, TGF-β signaling in DCs is critical in the control of autoimmunity through both Treg-dependent and -independent mechanisms, but it does not affect MHCII and costimulatory molecule expression.
Blockade of IL-10 Signaling during Bacillus Calmette-Guérin Vaccination Enhances and Sustains Th1, Th17, and Innate Lymphoid IFN-γ and IL-17 Responses and Increases Protection to Mycobacterium tuberculosis Infection
Authors: Pitt Jonathan M. , Stavropoulos Evangelos , Redford Paul S. , Beebe Amy M. , Bancroft Gregory J. , Young Douglas B. , O’Garra Anne
Published: September 2012

Vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the only prophylactic vaccine against tuberculosis, caused by Mycobacterium tuberculosis, but gives variable protection against pulmonary disease. The generation of host Th1 responses following BCG vaccination is accepted as the major mechanism of protection against M. tuberculosis infection. Early production of IL-17 in the lungs following M. tuberculosis challenge of mice previously vaccinated with M. tuberculosis peptides in adjuvant has been shown to be required for efficient Th1 cell recruitment. IL-10 regulates various processes involved in generation of Th1 and Th17 responses. Previous studies have shown IL-10 as a negative regulator of the immune response to primary M. tuberculosis infection, with Il10−/− mice having reduced lung bacterial loads. In this study we show that inhibition of IL-10 signaling during BCG vaccination enhances host-generated Ag-specific IFN-γ and IL-17A responses, and that this regimen gives significantly greater protection against aerogenic M. tuberculosis challenge in both susceptible and relatively resistant strains of mice. In M. tuberculosis-susceptible CBA/J mice, Ab blockade of IL-10R specifically during BCG vaccination resulted in additional protection against M. tuberculosis challenge of >1-log10 compared with equivalent isotype-treated controls. The protection observed following BCG vaccination concurrent with anti–IL-10R mAb treatment was sustained through chronic M. tuberculosis infection and correlated with enhanced lung Th1 and Th17 responses and increased IFN-γ and IL-17A production by γδ T cells and an innate-like Thy1.2+CD3− lymphoid population. We show that IL-10 inhibits optimal BCG-elicited protection, therefore suggesting that antagonists of IL-10 may be of great benefit as adjuvants in preventive vaccination against tuberculosis.
CD11c+ Cells Are Required for Antigen-Induced Increase of Mast Cells in the Lung
Authors: Dahlin Joakim S. , Feinstein Ricardo , Cui Yue , Heyman Birgitta , Hallgren Jenny
Published: September 2012

Patients with allergic asthma have more lung mast cells, which likely worsens the symptoms. In experimental asthma, CD11c+ cells have to be present during the challenge phase for several features of allergic inflammation to occur. Whether CD11c+ cells play a role for Ag-induced increases of lung mast cells is unknown. In this study, we used diphtheria toxin treatment of sensitized CD11c-diphtheria toxin receptor transgenic mice to deplete CD11c+ cells. We demonstrate that recruitment of mast cell progenitors to the lung is substantially reduced when CD11c+ cells are depleted during the challenge phase. This correlated with an impaired induction of endothelial VCAM-1 and led to a significantly reduced number of mature mast cells 1 wk after challenge. Collectively, these data suggest that Ag challenge stimulates CD11c+ cells to produce cytokines and/or chemokines required for VCAM-1 upregulation on the lung endothelium, which in turn is crucial for the Ag-induced mast cell progenitor recruitment and the increase in mast cell numbers.
Genetic Ablation of Arginase 1 in Macrophages and Neutrophils Enhances Clearance of an Arthritogenic Alphavirus
Authors: Stoermer Kristina A. , Burrack Adam , Oko Lauren , Montgomery Stephanie A. , Borst Luke B. , Gill Ronald G. , Morrison Thomas E.
Published: September 2012

Chikungunya virus (CHIKV) and Ross River virus (RRV) cause a debilitating, and often chronic, musculoskeletal inflammatory disease in humans. Macrophages constitute the major inflammatory infiltrates in musculoskeletal tissues during these infections. However, the precise macrophage effector functions that affect the pathogenesis of arthritogenic alphaviruses have not been defined. We hypothesized that the severe damage to musculoskeletal tissues observed in RRV- or CHIKV-infected mice would promote a wound-healing response characterized by M2-like macrophages. Indeed, we found that RRV- and CHIKV-induced musculoskeletal inflammatory lesions, and macrophages present in these lesions, have a unique gene-expression pattern characterized by high expression of arginase 1 and Ym1/Chi3l3 in the absence of FIZZ1/Relmα that is consistent with an M2-like activation phenotype. Strikingly, mice specifically deleted for arginase 1 in neutrophils and macrophages had dramatically reduced viral loads and improved pathology in musculoskeletal tissues at late times post-RRV infection. These findings indicate that arthritogenic alphavirus infection drives a unique myeloid cell activation program in inflamed musculoskeletal tissues that inhibits virus clearance and impedes disease resolution in an arginase 1-dependent manner.
B7x in the Periphery Abrogates Pancreas-Specific Damage Mediated by Self-reactive CD8 T Cells
Authors: Lee Jun Sik , Scandiuzzi Lisa , Ray Anjana , Wei Joyce , Hofmeyer Kimberly A. , Abadi Yael M. , Loke P’ng , Lin Juan , Yuan Jianda , Serreze David V. , Allison James P. , Zang Xingxing
Published: September 2012

B7x (B7-H4 or B7S1) is the seventh member of the B7 family, and its in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. In this study, we showed that B7x protein was not detected on APCs or T cells in both human and mice, which is unique in the B7 family. Because B7x protein is expressed in some peripheral cells such as pancreatic β cells, we used a CD8 T cell-mediated diabetes model (AI4αβ) in which CD8 T cells recognize an endogenous self-Ag, and found that mice lacking B7x developed more severe diabetes than control AI4αβ mice. Conversely, mice overexpressing B7x in the β cells (Rip-B7xAI4αβ) were diabetes free. Furthermore, adoptive transfer of effector AI4αβ CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4αβ mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4αβ mice. Although AI4αβ CD8 T cells in Rip-B7xAI4αβ and AI4αβ mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4αβ mice than in RIP-B7xAI4αβ mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells, and that local overexpression of B7x on pancreatic β cells is sufficient to abolish CD8 T cell-induced diabetes.
Autophagy Regulates IL-23 Secretion and Innate T Cell Responses through Effects on IL-1 Secretion
Authors: Peral de Castro Celia , Jones Sarah A. , Ní Cheallaigh Clíona , Hearnden Claire A. , Williams Laura , Winter Jan , Lavelle Ed C. , Mills Kingston H. G. , Harris James
Published: September 2012

Autophagy controls IL-1β secretion by regulating inflammasome activation and by targeting pro–IL-1β for degradation. In this article, we show that inhibition of autophagy, either with the PI3K inhibitors 3-methyladenine, wortmannin, and LY294002 or with small interfering RNA against autophagy proteins augmented the secretion of IL-23 by human and mouse macrophages and dendritic cells in response to specific TLR agonists. This process occurred at the transcriptional level and was dependent on reactive oxygen species and IL-1R signaling; it was abrogated with an IL-1R antagonist or with IL-1–neutralizing Abs, whereas treatment with either rIL-1α or IL-1β induced IL-23 secretion. Dendritic cells treated with LPS and 3-methyladenine secreted enhanced levels of both IL-1β and IL-23, and supernatants from these cells stimulated the innate secretion of IL-17, IFN-γ, and IL-22 by γδ T cells. These data demonstrate that autophagy has a potentially pivotal role to play in the induction and regulation of inflammatory responses by innate immune cells, largely driven by IL-1 and its consequential effects on IL-23 secretion.
Implications of the Regional Earthquake Likelihood Models test of earthquake forecasts in California
Authors: Sachs Michael Karl , Lee Ya-Ting , Turcotte Donald , Holliday James R. , Rundle John B.
Published: September 2012

The Regional Earthquake Likelihood Models (RELM) test was the first competitive comparison of prospective earthquake forecasts. The test was carried out over 5 years from 1 January 2006 to 31 December 2010 over a region that included all of California. The test area was divided into 7682 0.1°x0.1° spatial cells. Each submitted forecast gave the predicted numbers of earthquakes Nemi larger than M=4.95 in 0.1 magnitude bins for each cell. In this paper we present a method that separates the forecast of the number of test earthquakes from the forecast of their locations. We first obtain the number Nem of forecast earthquakes in magnitude bin m. We then determine the conditional probability λemi=Nemi/Nem that an earthquake in magnitude bin m will occur in cell i. The summation of λemi over all 7682 cells is unity. A random (no skill) forecast gives equal values of λemi for all spatial cells and magnitude bins. The skill of a forecast, in terms of the location of the earthquakes, is measured by the success in assigning large values of λemi to the cells in which earthquakes occur and low values of λemi to the cells where earthquakes do not occur. Thirty-one test earthquakes occurred in 27 different combinations of spatial cells i and magnitude bins m, we had the highest value of λemi for that mi cell. We evaluate the performance of eleven submitted forecasts in two ways. First, we determine the number of mi cells for which the forecast λemi was the largest, the best forecast is the one with the highest number. Second, we determine the mean value of λemi for the 27 mi cells for each forecast. The best forecast has the highest mean value of λemi. The success of a forecast during the test period is dependent on the allocation of the probabilities λemi between the mi cells, since the sum over the mi cells is unity. We illustrate the forecast distributions of λemi and discuss their differences. We conclude that the RELM test was successful in illustrating the choices required when a forecast of the location of a future earthquake is made.
Contests and the Private Production of Public Goods
Authors: Kolmar Martin , Wagener Andreas
Published: September 2012

The private provision of public goods generally suffers from two types of efficiency failures: sorting problems (the wrong individuals contribute) and quantity problems (an inefficient amount is provided). Embedding the provision game into a contest that rewards larger contributions with higher probabilities of winning a prize may remedy such failures. Applications include tenure decisions at universities, electoral competition among politicians, etc. We identify a tradeoff between the value of the prize and the decisiveness of the contest. High‐powered incentives in contests may cause an overprovision of the public good or wasteful participation of unproductive individuals in the contest.
Growth Patterns and Inequality in the Presence of Costly Technology Adoption
Authors: Lahiri Radhika , Ratnasiri Shyama
Published: September 2012

The stylized facts that motivate this article include the diversity in growth patterns that are observed across countries during the process of economic development and the divergence over time in income distributions both within and across countries. We construct a dynamic general equilibrium model in which technology adoption is costly and agents are heterogeneous in their initial holdings of resources. We interpret the adoption cost as the resources expended in acquiring skills associated with new technologies. Endogenous growth occurs in our model largely as a result of human capital deepening. The analytical results of the model characterize three growth outcomes associated with the technology adoption process depending on productivity differences between the technologies. These outcomes are labeled ‘poverty trap,’ ‘dual economy,’ and ‘balanced growth.’ The model is then capable of explaining the observed diversity in growth patterns in addition to the divergence of incomes over time and across countries.
Impact of Direct‐to‐Consumer Advertising on Pharmaceutical Prices and Demand
Authors: Dave Dhaval , Saffer Henry
Published: September 2012

Prescription drug expenditures are the fastest growing component of health care spending, rising threefold over the 1995–2007 period. Coinciding with this growth has been a surge in direct‐to‐consumer advertising (DTCA), made feasible by the Food and Drug Administrations's (FDA's) clarification of rules governing broadcast advertising in 1997 and 1999. We exploit this natural experiment to investigate the separate effects of broadcast and non‐broadcast DTCA on price and demand utilizing an extended monthly time series for all advertised and non‐advertised drugs in four therapeutic classes spanning 1994 through 2005, a period that enveloped the shifts in FDA guidelines and the consequent DTCA expansion. Controlling for physician‐directed promotion, fixed‐effects models indicate broadcast DTCA positively impacts own‐sales and price (elasticities of 0.10 and 0.05), while non‐broadcast DTCA has a relatively smaller impact. Expansions in broadcast DTCA account for 19% of the overall growth in drug expenditures, two‐thirds of this impact being driven by higher demand and the remainder due to higher prices.
Tratamiento del rechazo agudo hiperinmune con plasmaféresis y Rituximab. Nuestra Experiencia
Authors: Pérez Uceta Raquel , Llorente Sansano Mª Esther , Gálvez Velasco Mª de los Ángeles , Angüero Jurado Joseba Iñaki , Briceño Sánchez Gema , Bravo Moreno Mª Isabel
Published: September 2012

El trasplante renal consiste en la extracción de un riñón de un individuo sano y su colocación en un paciente con insuficiencia renal crónica terminal1. El rechazo inmunológico es la principal complicación tras el trasplante. Se denomina rechazo al conjunto de manifestaciones clínicas, funcionales, anatomopatológicas, que pueden aparecer en un receptor de trasplante renal, como consecuencia de la activación del sistema inmune contra el injerto. El rechazo puede aparecer desde el momento de revascularización del órgano hasta años más tarde2. La incidencia del rechazo dependerá esencialmente de dos factores: las características del receptor y el tratamiento inmunosupresor utilizado. En general se acepta que un 30-40% de los pacientes desarrollan algún episodio de rechazo en el trasplante inmediato (3 primeros meses)1. En la mayoría de los protocolos se utilizan como tratamiento convencional bolos de metil-prednisolona a dosis que varían entre 250 y 1.000mg/día, durante 3-4 días. Con esta pauta se consigue respuesta entre el 60-70% de los casos. En el resto de los casos se habla de rechazo corticoresistente2. La Plasmaferesis ha sido recientemente introducida en el tratamiento del rechazo agudo del trasplante renal resistente al tratamiento convencional con esteroides3. La aféresis puede definirse como una modalidad terapéutica que consiste en la extracción de un volumen determinado de plasma (de 2 a 5 litros) con el fin de eliminar aquellos patógenos considerados responsables de una enfermedad o bien sus manifestaciones clínicas. El recambio plasmático mediante filtración a través de membranas se realiza mediante el montaje de un circuito extracorpóreo.
Measurements of ambient HONO concentrations and vertical HONO flux above a northern Michigan forest canopy
Authors: Zhang N. , Zhou X. , Bertman S. , Tang D. , Alaghmand M. , Shepson P. B. , Carroll M. A.
Published: September 2012

Abstract. Systems have been developed and deployed at a North Michigan forested site to measure ambient HONO and vertical HONO flux. The modified HONO measurement technique is based on aqueous scrubbing of HONO using a coil sampler, followed by azo dye derivatization and detection using a long-path absorption photometer (LPAP). A Na2CO3-coated denuder is used to generate "zero HONO" air for background correction. The lower detection limit of the method, defined by 3 times of the standard deviation of the signal, is 1 pptv for 1-min averages, with an overall uncertainty of ±(1 + 0.05 [HONO]) pptv. The HONO flux measurement technique has been developed based on the relaxed eddy accumulation approach, deploying a 3-D sonic anemometer and two HONO measurement systems. The overall uncertainty is estimated to be within ±(8 × 10−8 + 0.15 FHONO) mol m−2 h−1, with a 20-min averaged data point per 30 min. Ambient HONO and vertical HONO flux were measured simultaneously at the PROPHET site from 17 July to 7 August 2008. The forest canopy was found to be a net HONO source, with a mean upward flux of 0.37 × 10−6 moles m−2 h−1. The HONO flux reached a maximal mean of ~0.7 × 10−6 moles m−2 h−1 around solar noon, contributing a major fraction to the HONO source strength required to sustain the observed ambient concentration of ~70 pptv. There were no significant correlations between [NOx] and daytime HONO flux and between JNO2 × [NO2] and HONO flux, suggesting that NOx was not an important precursor responsible for HONO daytime production on the forest canopy surface in this low-NOx rural environment. Evidence supports the hypothesis that photolysis of HNO3 deposited on the forest canopy surface is a major daytime HONO source.
An empirical model of global climate – Part 1: Reduced impact of volcanoes upon consideration of ocean circulation
Authors: Canty T. , Mascioli N. R. , Smarte M. , Salawitch R. J.
Published: September 2012

Abstract. Observed reductions in Earth's surface temperature following explosive volcanic eruptions have been used as a proxy for geo-engineering of climate by the artificial enhancement of stratospheric sulfate. Earth cools following major eruptions due to an increase in the reflection of sunlight caused by a dramatic enhancement of the stratospheric sulfate aerosol burden. Significant global cooling has been observed following the four major eruptions since 1900: Santa María, Mount Agung, El Chichón, and Mount Pinatubo, leading IPCC (2007) to state "major volcanic eruptions can thus cause a drop in global mean surface temperature of about half a degree Celsius that can last for months and even years". We use a multiple linear regression model applied to the global surface temperature anomaly to suggest that exchange of heat between the atmosphere and ocean, driven by variations in the strength of the Atlantic Meridional Overturning Circulation (AMOC), has been a factor in the decline of global temperature following these eruptions. The veracity of this suggestion depends on whether the Atlantic Multidecadal Oscillation (AMO) truly represents a proxy for the strength of the AMOC and the precise quantification of global cooling due to volcanoes depends on how the AMO is detrended. If the AMO is detrended using anthropogenic radiative forcing of climate, we find that surface cooling attributed to Mount Pinatubo, using the Hadley Centre/University of East Anglia surface temperature record, maximizes at 0.15 °C globally and 0.35 °C over land. These values are about a factor of 2 less than found when the AMO is neglected in the model and quite a bit lower than the canonical 0.5 °C cooling usually attributed to Pinatubo. The AMO had begun to decrease prior to the four major eruptions, suggesting that exchange of heat between the atmosphere and ocean due to variations in the strength of the AMOC drives the climate system, rather than responds to volcanic perturbations. The satellite record of atmospheric temperature from 1978 to present and other century-long surface temperature records are also consistent with our suggestion that volcanic cooling may have been over estimated by about a factor of 2 due to prior neglect of ocean circulation. Finally, a regression using AMO simulates pre-WWI cooling and WWII warming of global temperature particularly well, supporting the possibility that variations in the strength of the AMOC have truly exerted influence on global climate.
High-resolution NO2 remote sensing from the Airborne Prism EXperiment (APEX) imaging spectrometer
Authors: Popp C. , Brunner D. , Damm A. , Van Roozendael M. , Fayt C. , Buchmann B.
Published: September 2012

Abstract. We present and evaluate the retrieval of high spatial resolution maps of NO2 vertical column densities (VCD) from the Airborne Prism EXperiment (APEX) imaging spectrometer. APEX is a novel instrument providing airborne measurements of unique spectral and spatial resolution and coverage as well as high signal stability. In this study, we use spectrometer data acquired over Zurich, Switzerland, in the morning and late afternoon during a flight campaign on a cloud-free summer day in June 2010. NO2 VCD are derived with a two-step approach usually applied to satellite NO2 retrievals, i.e. a DOAS analysis followed by air mass factor calculations based on radiative transfer computations. Our analysis demonstrates that APEX is clearly sensitive to NO2 VCD above typical European tropospheric background abundances (>1 × 1015 molec cm−2). The two-dimensional maps of NO2 VCD reveal a very convincing spatial distribution with strong gradients around major NOx sources (e.g. Zurich airport, waste incinerator, motorways) and low NO2 in remote areas. The morning overflights resulted in generally higher NO2 VCD and a more distinct pattern than the afternoon overflights which can be attributed to the meteorological conditions prevailing during that day with stronger winds and hence larger dilution in the afternoon. The remotely sensed NO2 VCD are also in reasonably good agreement with ground-based in-situ measurements from air quality networks considering the limitations of comparing column integrals with point measurements. Airborne NO2 remote sensing using APEX will be valuable to detect NO2 emission sources, to provide input for NO2 emission modelling, and to establish links between in-situ measurements, air quality models, and satellite NO2 products.
Improving retrieval quality for airborne limb-sounders by horizontal regularisation
Authors: Ungermann J.
Published: September 2012

Abstract. Modern airborne infrared limb-sounders are capable of measuring profiles so fast that neighbouring profiles are very similar to one another. This can be exploited by retrieving whole 2-D cross-sections instead of simple 1-D profiles. By adding horizontal regularisation in addition to a potentially reduced vertical regularisation, vertical structures can be better retrieved while maintaining or reducing the general noise level. This paper presents algorithms that are able to perform such a retrieval and efficiently produce typical diagnostic quantities. The characteristics of produced retrieval results for a variety of parametrisations is discussed in a case study that analyses a cross-section measured by the CRISTA-NF instrument during the RECONCILE campaign between Spitsbergen and Kiruna, Sweden, in March 2010. It is shown that cross-section retrievals can either reduce noise or produce finer vertical structures while maintaining the same noise level. The presented methodology can also be applied in a straightforward way to improve the retrievals for both near-future satellite-borne limb-sounders and current air- and satellite-borne nadir sounder.
Detecting an external influence on recent changes in oceanic oxygen using an optimal fingerprinting method
Authors: Andrews O. D. , Bindoff N. L. , Halloran P. R. , Ilyina T. , Le Quéré C.
Published: September 2012

Abstract. Ocean deoxygenation has been observed in all major ocean basins over the past 50 yr. Although this signal is largely consistent with oxygen changes expected from anthropogenic climate change, the contribution of external forcing to recent deoxygenation trends relative to natural internal variability is yet to be established. Here we conduct a formal optimal fingerprinting analysis to investigate if external forcing has had a detectable influence on observed dissolved oxygen concentration ([O2]) changes between ~ 1970 and ~ 1992 using simulations from two Earth System Models (MPI-ESM-LR and HadGEM2-ES). We detect a response to external forcing at a 90% confidence level and find that observed [O2] changes are inconsistent with internal variability as simulated by models. This result is robust in the global ocean for depth-averaged (1-D) zonal mean patterns of [O2] change in both models. Further analysis with the MPI-ESM-LR model shows similar positive detection results for depth-resolved (2-D) zonal mean [O2] changes globally and for the Pacific Ocean individually. Observed oxygen changes in the Atlantic Ocean are indistinguishable from natural internal variability. Simulations from both models consistently underestimate the amplitude of historical [O2] changes in response to external forcing, suggesting that model projections for future ocean deoxygenation may also be underestimated.