bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding Transport Demand Management and Its Role in Delivery of Sustainable Urban Transport
Authors: Black Colin S. , Schreffler Eric N.
Published: October 2010

Outdated notions of transport demand management (TDM) as a collection of vaguely related initiatives are constraining the true potential of the concept. This paper explains how TDM is far more effective when it is framed as a philosophical approach that in time is likely to become a cornerstone of sustainable urban transport systems. A new paradigm internationally recognized as TDM is emerging in transport planning. This new paradigm embraces under its umbrella concepts commonly referred to as mobility management, smarter choices, and active travel management. Transport professionals worldwide have been collaborating to update the understanding of TDM as a philosophy that underpins the approach to improving the sustainability of transport. A review of TDM internationally demonstrated the importance of combining a number of key aspects to an effective strategy. Key to the successful transfer of sustainable urban transport policies is integrating the TDM philosophy into urban transport planning, as well as the daily management and operation of transport services and infrastructure. The paper presents a powerful policy tool developed to assist with this process of integration, the Mobility Enhancement and Trip Reduction Index to Aid Comparison (METRIC). METRIC is used internationally to benchmark comparative progress on the implementation of TDM.
Estimating the Potential Success of Sustainable Transport Measures for a Small Town
Authors: Farrell Séona , McNamara David , Caulfield Brian
Published: October 2010

This paper examines the benefits of promoting and encouraging the use of soft modes of transport in a small town in Ireland. Currently, in the town in question, almost 70% drive to work alone each day. The Irish government recently adopted a policy of actively promoting and developing sustainable towns through the use of soft transport measures. This paper takes a typical town in Ireland and demonstrates how a modal shift toward sustainable transport measures could result in substantial savings in vehicle kilometers traveled and carbon dioxide (CO2) emissions. Census data were used to estimate the benefits of a modal shift from driving alone to walking, cycling, and carpooling. The COPERT IV model was used to estimate the reductions in CO2 emissions if the estimated modal shifts were realized. Analysis of the commuting patterns of the individuals in the study area shows that the majority of car trips are less than 6 km. The results of the paper show that no one soft measure promoted in isolation is the silver bullet; rather, a mix of these options would be optimal for achieving a modal shift.
Sustainable Transport in France
Authors: Lopez-Ruiz Hector G. , Crozet Yves
Published: October 2010

Today numerous published works conclude that transport seems to be completely coupled to economic and export–import growth. Therefore, as a direct consequence of economic development, transport is one of the major final energy consumers and one of the most important sources of carbon dioxide (CO2) emissions. Consequently, continuous increases in emissions by the transport sector pose an environmental problem. This paper assesses possible solutions through scenario building in a backcasting manner by using the Transport Issues in the Long Term model. In particular, three scenarios that address how technology and various public policies can contribute to a sharp reduction in CO2 emissions are evaluated. Furthermore, estimates of infrastructure investment needs as well as insight into how transport budgets (time and monetary) could evolve in each of the following three scenarios presented are proposed: the Pegasus scenario, in which strict technology standards are promoted; the Chronos scenario, in which green multimodalities are promoted; and the Hestia scenario, in which the decoupling of transport and growth in the gross domestic product is promoted. Each scenario allows the types of results that can be obtained through different policy mixes to be quickly comprehended. In sum, a realistic technological hypothesis shows that a 50% reduction in emissions from the 2000 level is a clear possibility and that the remaining 25% needed to reach the total French target emissions reduction of 75% is possible through the use of different types of policy mixes.
Impact of Transport Infrastructure on Firm Formation
Authors: Melo Patricia C. , Graham Daniel J. , Noland Robert B.
Published: October 2010

This paper investigates the relationship between the availability of transport infrastructure and new plant openings in Portugal. The paper estimates an econometric model that uses plant-level data and geographic information systems to test whether denser motorway and railway networks have a positive effect on the formation of firms in Portuguese municipalities for various sectors of the economy. In addition to a study of the role of the own-municipality transport infrastructure, tests for the presence of spatial spillovers from the transport infrastructure were also conducted. The results suggest that both the railway and the motorway networks act as determinants of new plant openings. Expanding the local municipality railway and motorway networks by 10% can produce an increase in new plant openings from 0.9% to 2.7% and 0.7% to 2.6%, respectively. Positive spatial spillover effects from the transport infrastructure were also found: improving the motorway and railway networks of neighboring municipalities by 10% increases plant openings by from 2.7% to 5.1% and 2.4% to 6.7%, respectively.
Gender and sexuality: the discursive limits of 'equality' in higher education
Authors: Morrish Liz , Sauntson Helen
Published: October 2010

This special issue sets out to investigate a number of areas of concern, regarding gender and sexuality, which are identifiable in the current British higher education environment. We argue that current dominant 'neoliberal' discourses, which emphasise the commodification of higher education in the U.K., function to set limits upon 'equality'. While these discourses often suggest a widening of opportunities within higher education, with an emphasis upon unlimited individual freedom and choice, the lived experience can be rather different for women and sexual minorities. This issue explores the impact such discourses are having upon gender and sexuality identities and practices in the academy.
Origin of the outburst flood from Glacier de Tête Rousse in 1892 (Mont Blanc area, France)
Authors: Vincent C. , Garambois S. , Thibert E. , Lefèbvre E. , Le Meur E. , Six D.
Published: October 2010

Extensive field measurements and historical data have been used to re-analyse the cause of the outburst flood from Glacier de Tête Rousse that devastated the village of Saint-Gervais–Le Fayet, French Alps in 1892, causing 175 fatalities. The origin of this disaster was the rupture of an intraglacial cavity in Glacier de Tête Rousse that released 200 000 m3of water and ice. All previous studies have concluded that the intraglacial cavity was formed from a crevasse that was filled and enlarged by meltwater. The re-analysis presented here suggests that the reservoir of the upper cavity did not originate as an enlarging crevasse. The origin of the meltwater reservoir was more likely a supraglacial lake formed before 1878 during a period of negative mass balance. Following a period of positive mass balance after 1878, the lake was hidden until the outburst flood of 1892. This means that such hazards may be detected by checking regularly for the formation of a lake on the surface of the glacier before it is hidden.
Light propagation in firn: application to borehole video
Authors: Fudge T.J. , Smith Benjamin E.
Published: October 2010

Borehole optical stratigraphy (BOS) is a borehole video system and processing routine for investigating polar firn. BOS records brightness variations in the firn and is effective at identifying stratigraphic markers. BOS brightness logs have been used to count annual layers and measure vertical strain, even though a specific cause of the brightness variations has not been determined. Here we combine two models of light transport to examine potential errors with BOS and identify improvements which will allow the system to estimate optical grain size. We use a Monte Carlo radiative transfer model to estimate the influence of firn microstructure variations on borehole reflectance. We then use a ray-tracing algorithm to model the multiple reflections within the borehole that cause measured brightness variations. Multiple reflections cause the brightness measured at a point on the borehole wall to not necessarily be equal to the local wall reflectance. The ray tracing further shows that wall imperfections or variations in the camera position can produce brightness variations that are unrelated to changes in firn properties. Smooth walls and good stabilization of the camera help ensure that brightness variations result from variations in firn properties, and thus are a measure of firn stratigraphy, rather than artifacts.
Present stability of the Larsen C ice shelf, Antarctic Peninsula
Authors: Jansen D. , Kulessa B. , Sammonds P.R. , Luckman A. , King E.C. , Glasser N.F.
Published: October 2010

We modelled the flow of the Larsen C and northernmost Larsen D ice shelves, Antarctic Peninsula, using a model of continuum mechanics of ice flow, and applied a fracture criterion to the simulated velocities to investigate the ice shelf’s present-day stability. Constraints come from satellite data and geophysical measurements from the 2008/09 austral summer. Ice-shelf thickness was derived from BEDMAP and ICESat data, and the density–depth relationship was inferred from our in situ seismic reflection data. We obtained excellent agreements between modelled and measured ice-flow velocities, and inferred and observed distributions of rifts and crevasses. Residual discrepancies between regions of predicted fracture and observed crevasses are concentrated in zones where we assume a significant amount of marine ice and therefore altered mechanical properties in the ice column. This emphasizes the importance of these zones and shows that more data are needed to understand their influence on ice-shelf stability. Modelled flow velocities and the corresponding stress distribution indicate that the Larsen C ice shelf is stable at the moment. However, weakening of the elongated marine ice zones could lead to acceleration of the ice shelf due to decoupling from the slower parts in the northern inlets and south of Kenyon Peninsula, leading to a velocity distribution similar to that in the Larsen B ice shelf prior to its disintegration.
Basal melt rates beneath Whillans Ice Stream, West Antarctica
Authors: Beem Lucas H. , Jezek Ken C. , Van Der Veen C.J.
Published: October 2010

Basal water lubricates and enables the fast flow of the West Antarctic ice streams which exist under low gravitational driving stress. Identification of sources and rates of basal meltwater production can provide insight into the dynamics of ice streams and the subglacial hydrology, which remain insufficiently described by glaciological theory. Combining measurements and analytic modeling, we identify two regions where basal meltwater is produced beneath Whillans Ice Stream, West Antarctica. Downstream of the onset of shear crevasses, strong basal melt (20–50 mm a−1) is concentrated beneath the relatively narrow shear margins. Farther upstream, melt rates are consistently 3–7 mm a−1 across the width of the ice stream. We show that the transition in melt-rate patterns is coincident with the onset of shear margin crevassing and streaming flow and related to the development of significant lateral shear resistance, which reorganizes the resistive stress regime and induces a concentration of basal resistance adjacent to the shear margin. Finally, we discuss how downstream freeze-on in the ice-stream center coupled with melt beneath the shear margin might result in a slowing but widening ice stream.
The importance of considering depth-resolved photochemistry in snow: a radiative-transfer study of NO2 and OH production in Ny-Ålesund (Svalbard) snowpacks
Authors: France J.L. , King M.D. , Lee-Taylor J.
Published: October 2010

Solar visible radiation can penetrate 2–30 cm (e-folding depth) into snowpacks and photolyse nitrate anions and hydrogen peroxide contained in the snow. Photolysis rate coefficients, J, for NO3− and H2O2 photolysis are presented for a melting and a fresh snowpack at Ny-Ålesund, Svalbard. Calculations of (a) transfer velocities, υ, and molecular fluxes of gaseous NO2 from the snowpack and (b) depth-integrated production rates of OH radicals within the snowpack are presented. The results show the importance of considering the depth dependence, i.e. not just the snow surface, when modelling snowpack photochemistry. Neglecting photochemistry under the snow surface can result in an apparent larger molecular flux of NO2 from NO3− photolysis than the melting snowpack. However, when the depth-resolved molecular fluxes of NO2 within the snowpack are calculated, a larger NO2 flux may be apparent in the melting snowpack than the fresh snowpack. For solar zenith angles of 60°, 70° and 80° the modelled molecular fluxes of NO2 from fresh snowpack are 11.6, 5.6 and 1.7 nmol m−2 h−1, respectively, and those for melting snowpack are 19.7, 9.1 and 2.9 nmol m−2 h−1, respectively.
Comparison of satellite, thermochron and air temperatures at Summit, Greenland, during the winter of 2008/09
Authors: Koenig Lora S. , Hall Dorothy K.
Published: October 2010

Current trends show a rise in Arctic surface and air temperatures, including over the Greenland ice sheet where rising temperatures will contribute to increased sea-level rise through increased melt. We aim to establish the uncertainties in using satellite-derived surface temperature for measuring Arctic surface temperature, as satellite data are increasingly being used to assess temperature trends. To accomplish this, satellite-derived surface temperature, or land-surface temperature (LST), must be validated and limitations of the satellite data must be assessed quantitatively. During the 2008/09 boreal winter at Summit, Greenland, we employed data from standard US National Oceanic and Atmospheric Administration (NOAA) air-temperature instruments, button-sized temperature sensors called thermochrons and the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite instrument to (1) assess the accuracy and utility of thermochrons in an ice-sheet environment and (2) compare MODIS-derived LSTs with thermochron-derived surface and air temperatures. The thermochron-derived air temperatures were very accurate, within 0.1 ± 0.3°C of the NOAA-derived air temperature, but thermochron-derived surface temperatures were ∼3°C higher than MODIS-derived LSTs. Though surface temperature is largely determined by air temperature, these variables can differ significantly. Furthermore, we show that the winter-time mean air temperature, adjusted to surface temperature, was ∼11°C higher than the winter-time mean MODIS-derived LST. This marked difference occurs largely because satellite-derived LSTs cannot be measured through cloud cover, so caution must be exercised in using time series of satellite LST data to study seasonal temperature trends.
Introduction: Collective Knowledge and Science
Authors: Wray K. Brad
Published: October 2010

The literature on collective belief and collective intentionality has grown rapidly and is now quite extensive. Philosophers have applied the concepts of “collective belief” and “collective intentionality” in a variety of contexts, including political and legal contexts as well as scientific contexts, specifically to model the behavior of research teams and scientific specialties.
Joint Acceptance and Scientific Change: A Case Study
Authors: Andersen Hanne
Published: October 2010

Recently, several scholars have argued that scientists can accept scientific claims in a collective process, and that the capacity of scientific groups to form joint acceptances is linked to a functional division of labor between the group members. However, these accounts reveal little about how the cognitive content of the jointly accepted claim is formed, and how group members depend on each other in this process. In this paper, I shall therefore argue that we need to link analyses of joint acceptance with analyses of distributed cognition. To sketch how this can be done, I shall present a detailed case study, and on the basis of the case, analyze the process through which a group of scientists jointly accept a new scientific claim and at a later stage jointly accept to revise previously accepted claims. I shall argue that joint acceptance in science can be established in situations where an overall conceptual structure is jointly accepted by a group of scientists while detailed parts of it are distributed among group members with different areas of expertise, a condition that I shall call a heterogeneous conceptual consensus. Finally, I shall show how a heterogeneous conceptual consensus can work as a constraint against scientific change and address the question how changes may nevertheless occur.
Disorderly Damsels? Women and Interpersonal Violence in Pre-Reformation Scotland
Authors: Ewan Elizabeth
Published: October 2010

This study uses the court records of eight pre-Reformation Scottish towns to examine women's involvement as perpetrators of violent physical assaults in their communities. It examines the nature of the assaults, including whether women were more likely to act alone or with others, the role of family and household, the types of victims, and the weapons used. These matters are compared to patterns found in studies of women's violence elsewhere in contemporary Europe. The article also examines how the community and women themselves perceived their use of physical assault. For example, some could justify violence as an acceptable method of discipline. Many attacks were aimed not only at causing physical harm but were also assaults on the victim's honour; a study of assault thus helps shed light on the nature of male and female honour among ordinary townsfolk in late medieval Scotland.
Commemoration of the South African War in Scotland, 1900–10
Authors: McFarland E. W.
Published: October 2010

This article focuses on Scotland's engagement with the imperial project through the medium of its commemoration of the second South African War. It focuses on both the process of commemoration and its outputs. These included a rich and varied range of military and civic memorials, some traditionally monumental, others with a more functional intent, including educational and welfare projects. The collective memory of the war which they articulated drew overwhelmingly on Scots' perceptions of themselves as a ‘marital race’. However, the discussion also highlights the plurality of memory and the multi-layering of the commemorative experience. Thus memorials both honoured the fallen and proclaimed the justice of their cause, but the balance of their messages would shift over time, while remaining open to differing interpretations by a range of constituencies, such as grieving families, regimental comrades and civic leaders.
Mechanisms of Cisplatin Nephrotoxicity
Authors: Miller Ronald P. , Tadagavadi Raghu K. , Ramesh Ganesan , Reeves William Brian
Published: October 2010

Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.
Paradise Without People: Exclusive Destination Promotion
Authors: Echtner Charlotte M.
Published: October 2010

Certain stereotypes exist about island destinations, especially the so-called “tropical island paradise.” There are also stereotypical depictions of the inhabitants of these places that either emphasize or exclude certain characteristics and roles. This article examines
the portrayal of people in the tropical island destination of Mauritius. By conducting a detailed content analysis of a sample of tourist brochures, two significant exclusions in the representation of Mauritius are uncovered. Firstly, Mauritius is portrayed as being mostly devoid of people
and secondly, there is an obscuration of the diverse ethnicity of the local population. Using postcolonial theory, the practical and ideological implications of such “exclusive” destination promotions are discussed, drawing particular attention to the origins and control of these
representations. It is argued that these representational issues have relevance not only for Mauritius but also for other “island paradises.”
Burnishing Nationalism: Touring Burns and Authenticity in Scotland
Authors: Bhandari Kalyan
Published: October 2010

This article argues that museums are an effective tool in the assertion of a sense of nationhood. In order to validate this argument this article examines the question of authenticity in three museums in the southwest of Scotland dedicated to Robert Burns and how they convey a sense
of nationhood. Examples have been used to show how an authentic past is narrated to visitors, including the presentation of artifacts that are reproductions or unoriginal, the use of language in brochures that are an assertion of the past, and restoration efforts in the town of Dumfries. The
data collected at the three museums compiled from the author's field notes indicate that Scotland is presented as primordial, ancient, original, and distinctive—all of which are concepts associated with nationalism. Given Robert Burns' reputation as an iconic national figure, the role
of authenticity in the museums plays a semiotic role in presenting a symbolic version of national identity.
Other tetraploid species and conspecific diploids as sources of genetic variation for an autotetraploid
Authors: Stift Marc , Bregman Rob , Oostermeijer J. Gerard B. , van Tienderen Peter H.
Published: October 2010

•Premise of the study:Most plants are polyploid and have more than two copies of the genome. The evolutionary success of polyploids is often attributed to their potential to harbor increased genetic variation, but it is poorly understood how polyploids can attain such variation. Because of their formation bottleneck, newly formed tetraploids start out with little variation. Tetraploids may attain genetic variation through a combination of new mutations, recurrent formation, and gene exchange with diploid ancestors or related tetraploid species. We explore the role of gene exchange and introgression in autotetraploidRorippa amphibia, a species that harbors more genetic variation than its diploid ancestors.

•Methods:We crossed autotetraploidR. amphibiato diploid conspecifics and tetraploidR. sylvestrisand backcrossed resulting F1hybrids. We used flow cytometry to determine the ploidy of all progeny.

•Key results:Tetraploids ofR. amphibiaandR. sylvestriswere interfertile; F1hybrids were fertile and could backcross. Crosses between diploids and tetraploids yielded a small number of viable, often tetraploid progeny. This indicates that unreduced gametes can facilitate gene flow from diploids to tetraploids. We detected a frequency of unreduced gametes of around 2.7 per 1000, which was comparable between diploids and tetraploids.

•Conclusions:Introgression from tetraploidR. sylvestrisprovides a realistic source of variation in autotetraploidR. amphibia. Only in a scenario where other compatible partners are absent, for example immediately after tetraploidization, gene flow through unreduced gametes from diploids could be an important source of genetic variation for tetraploids.
COLLAGEN COUPLED WITH HYALURONIC: SYNTHESIS AND SOFT TISSUE FILLER APPLICATION
Authors: Tung Kwang Yi , Lee Ming Wei
Published: October 2010

Injectable filler, which is often applied in minimally invasive surgery, has been widely-used in facial rejuvenation. Because of its convenience, effective usage and less downtime after treatment for the patients, it becomes one of the most popular treatment methods at present. The currently available products containing collagen base have been proven to have much satisfactory safety and effectiveness, but one of its disadvantages is the lack of long-term volume persistence. We have previously prepared the reconstituted collagen fibrils with hyaluronic acid (HA) by modifying the fibril surface. This study is to evaluate the potential of these materials as injectable filler in vitro. A preparation of collagen fibrils with a diameter of 100–150 nm was used. The modification rate of HA on the fibril surface was 20%. In assessment of the biocompatibility, it was proven that the collagen fibril and HA-collagen fibril treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) had no cytotoxicity or inhibitory actions. In interactions between these materials and cells, it was found that the existence of HA could improve the migration ability of L929 fibroblasts and breast cancer cells (MDA-MB 435s). In conclusion, collagen fibril and HA-collagen fibril have the potential to be developed into an injection as a soft tissue filler for biomedical applications.
A NEW MATHEMATICAL APPROACH FOR DETECTION OF ACTIVE AREA IN HUMAN BRAIN fMRI USING NONLINEAR MODEL
Authors: Taalimi Ali , Fatemizadeh Emad
Published: October 2010

Functional magnetic resonance imaging (fMRI) is widely-used for detection of the brain's neural activity. The signals and images acquired through this imaging technique demonstrate the human brain's response to pre-scheduled tasks. Several studies on blood oxygenation level-dependent (BOLD) signal responses demonstrate nonlinear behavior in response to a stimulus. In this paper we propose a new mathematical approach for modeling BOLD signal activity, which is able to model nonlinear and time variant behaviors of this physiological system. We employ the Nonlinear Auto Regressive Moving Average (NARMA) model to describe the mathematical relationship between output signals and predesigned tasks. The model parameters can be used to distinguish between rest and active states of a brain region. We applied our proposed method for active region detection on real as well as simulated data sets. The results show superior performance in comparison with existing methods.
THE INFLUENCE OF SURFACE ROUGHNESS AND CEMENTING TECHNIQUE ON THE MICROSTRUCTURE AND MECHANICAL STRENGTH AT THE CEMENT-PROSTHESIS INTERFACE
Authors: Tai Ching-Lung , Lee De-Mei , Hsieh Pang-Hsing
Published: October 2010

It was generally considered that a femoral stem with a rough surface was not suitable for cemented fixation in total hip arthroplasty. The long-term follow-up studies on the cemented rough stems clearly revealed a significantly higher loosening and revision rate than those of polished stems. However, from a biomechanics point of view, a rough surface might result in stronger cement-prosthesis bonding because of micro-interlocking between the bone cement and the stem. This contradiction between biomechanical standpoint and clinical observation remains as a problem to be resolved. Thus, this study was designed to evaluate the effect of stem surface roughness and the cement pre-coating process on the bonding strength of the prosthesis-cement interface. A total of 48 Co-Cr rods with three different levels of surface roughness (polished, plasma-treated and bead-coated, 16 in each group) were enrolled in the study. All specimens were cylindrical in shape with lengths of 120 mm and 12 mm diameters. Sixteen specimens in each group were then treated with non-precoated or precoated cement fixation (8 in each group). After fixing the Co-Cr rod, the pushout test was carried out using a MTS testing machine, and the shear strength for each group was compared. An additional microscopic observation of the metal/cement interface was also performed. The results of the pushout test indicated that the shear strength increased with increasing implant surface roughness, regardless of whether or not the stem was treated with the cement precoating process. However, stem precoating did not statistically improve the bonding strength at each level of surface roughness. Microscopic observation of the stem-cement interfaces revealed that the bone cement significantly infiltrated the rough surface in both the precoated and non-precoated groups with stems with various levels of surface roughness. Surface roughness of the femoral stem significantly affected the stem/cement interface, improving shear strength significantly. Stem precoating did not statistically improve the shear strength using the present cementing technique with retrograde high-pressure injection. Although a high surface roughness of the femoral stem appears to be an effective choice to improve implant fixation in cemented THA, the longevity of the prostheses implanted with such a stem can only be determined from long-term clinical trials.
Inhibition of Terminal Differentiation of B Cells Mediated by CD27 and CD40 Involves Signaling through JNK
Authors: Satpathy Shuchismita , Shenoy Gautam N. , Kaw Sheetal , Vaidya Tushar , Bal Vineeta , Rath Satyajit , George Anna
Published: October 2010

B cells responding to cognate Ag in vivo undergo clonal expansion that is followed by differentiation into Ab-secreting plasma cells or into quiescent restimulable memory. Both these events occur in the germinal center and require that cells exit from proliferation, but the signals that lead to one or the other of these mutually exclusive differentiation pathways have not been definitively characterized. Previous experiments have shown that signals transduced through the TNFRs CD27 and CD40 at the time of B cell stimulation in vitro or in vivo can influence this cell fate decision by inhibiting terminal differentiation and promoting memory. In this study, we show that the PIQED domain of the cytoplasmic tail of murine CD27 and the adapter molecule TNFR-associated factor 2 are involved in this effect. Using pharmacological inhibitors of signaling intermediates, we identify JNK as being necessary and sufficient for the observed inhibition of terminal differentiation. While JNK is involved downstream of CD40, inhibition of the MEK pathway can also partially restore plasma cell generation, indicating that both signaling intermediates may be involved. We also show that inhibition of induction of IFN regulatory factor 4 and B lymphocyte induced maturation protein 1 are downstream events common to both receptors.
The Interactions of Multiple Cytokines Control NK Cell Maturation
Authors: Brady Jason , Carotta Sebastian , Thong Rebecca P. L. , Chan Christopher J. , Hayakawa Yoshihiro , Smyth Mark J. , Nutt Stephen L.
Published: October 2010

Although NK cells are well known for their cytotoxic functions, they also produce an array of immunoregulatory cytokines and chemokines. During an immune response, NK cells are exposed to complex combinations of cytokines that influence their differentiation and function. In this study, we have examined the phenotypic and functional consequences of exposing mouse NK cells to IL-4, IL-12, IL-15, IL-18, and IL-21 and found that although all factors induced signs of maturation, characterized by decreased proliferation and IFN-γ secretion, distinct combinations induced unique cytokine secretion profiles. In contrast, the immunosuppressive factors IL-10 and TGF-β had little direct effect on NK cell effector functions. Sustained IL-18 signals resulted in IL-13 and GM-CSF production, whereas IL-12 and IL-21 induced IL-10 and TNF-α. Surprisingly, with the exception of IL-21, all cytokines suppressed cytotoxic function of NK cells at the expense of endogenous cytokine production suggesting that “helper-type” NK cells were generated. The cytokine signals also profoundly altered the cell surface phenotype of the NK cells—a striking example being the downregulation of the activating receptor NKG2D by IL-4 that resulted in decreased NKG2D-dependent killing. IL-4 exposure also modulated NKG2D expression in vivo suggesting it is functionally important during immune responses. This study highlights the plasticity of NK cell differentiation and suggests that the relative abundance of cytokines at sites of inflammation will lead to diverse outcomes in terms of NK cell phenotype and interaction with the immune system.
Eotaxin-3/CC Chemokine Ligand 26 Is a Functional Ligand for CX3CR1
Authors: Nakayama Takashi , Watanabe Yoshiko , Oiso Naoki , Higuchi Tomonori , Shigeta Akiko , Mizuguchi Nobuyuki , Katou Fuminori , Hashimoto Kenji , Kawada Akira , Yoshie Osamu
Published: October 2010

Eotaxin-3/CCL26 is a functional ligand for CCR3 and abundantly produced by IL-4–/IL-13–stimulated vascular endothelial cells. CCL26 also functions as a natural antagonist for CCR1, CCR2, and CCR5. In this study, we report that CCL26 is yet a functional ligand for CX3CR1, the receptor for fractalkine/CX3CL1, which is expressed by CD16+ NK cells, cytotoxic effector CD8+ T cells, and CD14lowCD16high monocytes. Albeit at relatively high concentrations, CCL26 induced calcium flux and chemotaxis in mouse L1.2 cells expressing human CX3CR1 but not mouse CX3CR1 and competed with CX3CL1 for binding to CX3CR1. In chemotaxis assays using human PBMCs, CCL26 attracted not only eosinophils but also CD16+ NK cells, CD45RA+CD27−CD8+ T cells, and CD14lowCD16high monocytes. Intraperitoneal injection of CCL26 into mice rapidly recruited mouse eosinophils and intravenously transferred human CD16+ NK cells into the peritoneal cavity. IL-4–stimulated HUVECs produced CCL26 and efficiently induced adhesion of cells expressing CX3CR1. Real-time PCR showed that skin lesions of psoriasis consistently contained CX3CL1 mRNA but not CCL26 mRNA, whereas those of atopic dermatitis contained CCL26 mRNA in all samples but CX3CL1 mRNA in only about half of the samples. Nevertheless, the skin lesions from both diseases consistently contained CX3CR1 mRNA at high levels. Thus, CCL26 may be partly responsible for the recruitment of cells expressing CX3CR1 in atopic dermatitis particularly when the expression of CX3CL1 is low. Collectively, CCL26 is another agonist for CX3CR1 and may play a dual role in allergic diseases by attracting eosinophils via CCR3 and killer lymphocytes and resident monocytes via CX3CR1.
Hepatitis C Virus Inhibits DNA Damage Repair through Reactive Oxygen and Nitrogen Species and by Interfering with the ATM-NBS1/Mre11/Rad50 DNA Repair Pathway in Monocytes and Hepatocytes
Authors: Machida Keigo , McNamara George , Cheng Kevin T.-H. , Huang Jeffrey , Wang Chun-Hsiang , Comai Lucio , Ou Jing-Hsiung James , Lai Michael M. C.
Published: October 2010

Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma and putatively also non-Hodgkin’s B cell lymphoma. In this study, we demonstrated that PBMCs obtained from HCV-infected patients showed frequent chromosomal aberrations and that HCV infection of B cells in vitro induced enhanced chromosomal breaks and sister chromatid exchanges. HCV infection hypersensitized cells to ionizing radiation and bleomycin and inhibited nonhomologous end-joining repair. The viral core and nonstructural protein 3 proteins were shown to be responsible for the inhibition of DNA repair, mediated by NO and reactive oxygen species. Stable expression of core protein induced frequent chromosome translocations in cultured cells and in transgenic mice. HCV core protein binds to the NBS1 protein and inhibits the formation of the Mre11/NBS1/Rad50 complex, thereby affecting ATM activation and inhibiting DNA binding of repair enzymes. Taken together, these data indicate that HCV infection inhibits multiple DNA repair processes to potentiate chromosome instability in both monocytes and hepatocytes. These effects may explain the oncogenicity and immunological perturbation of HCV infection.
A Critical Role for C5L2 in the Pathogenesis of Experimental Allergic Asthma
Authors: Zhang Xun , Schmudde Inken , Laumonnier Yves , Pandey Manoj. K. , Clark Jennifer R. , König Peter , Gerard Norma P. , Gerard Craig , Wills-Karp Marsha , Köhl Jörg
Published: October 2010

The complement fragment C5a plays dual roles in the development of experimental allergic asthma. It protects from pulmonary allergy by a regulatory effect on dendritic cells during allergen sensitization, but is proallergic during the effector phase. C5a can bind to two distinct receptors (i.e., C5a receptor and C5a receptor-like 2 [C5L2]). The functional role of C5L2 in vivo remains enigmatic. In this study, we show in two models of OVA- and house dust mite (HDM)-induced experimental allergic asthma that C5L2-deficient mice are protected from the development of airway hyperresponsiveness, Th2 cytokine production, eosinophilic airway inflammation, serum IgE, or mucus production. Surprisingly, HDM-induced experimental asthma in C5L2-deficient mice was associated with increased pulmonary IL-17A production and increased airway neutrophil numbers. To directly assess the role of C5L2 on myeloid dendritic cells (mDCs) during allergen sensitization, we performed single or repeated adoptive transfers of C5L2-deficient mDCs into wild-type mice. HDM-pulsed C5L2-deficient mDCs induced strong Th2 cytokine production, which was associated with marked IFN-γ and IL-17A production, decreased eosinophil numbers, and reduced IgE production as compared with HDM-pulsed mDCs from wild-type mice. HDM stimulation of C5L2−/− mDCs in vitro resulted in production of Th17-promoting cytokine IL-23, which was absent in wild-type mDCs. Our findings suggest that C5L2 acts at the mDC/T cell interface to control the development of Th1 and Th17 cells in response to airway HDM exposure. Furthermore, it drives Th2 immune responses independent of mDCs, suggesting a complex role for C5L2 in the development of experimental allergic asthma.
Neutrophil Migration across Intestinal Epithelium: Evidence for a Role of CD44 in Regulating Detachment of Migrating Cells from the Luminal Surface
Authors: Brazil Jennifer C. , Lee Winston Y. , Kolegraff Keli N. , Nusrat Asma , Parkos Charles A. , Louis Nancy A.
Published: October 2010

The migration of polymorphonuclear leukocytes (PMNs) across the intestinal epithelium is a histopathological hallmark of many mucosal inflammatory diseases including inflammatory bowel disease. The terminal transmigration step is the detachment of PMNs from the apical surface of the epithelium and their subsequent release into the intestinal lumen. The current study sought to identify epithelial proteins involved in the regulation of PMN migration across intestinal epithelium at the stage at which PMNs reach the apical epithelial surface. A panel of Abs reactive with IFN-γ–stimulated T84 intestinal epithelial cells was generated. Screening efforts identified one mAb, GM35, that prevented PMN detachment from the apical epithelial surface. Microsequencing studies identified the GM35 Ag as human CD44. Transfection studies confirmed this result by demonstrating the loss of the functional activity of the GM35 mAb following attenuation of epithelial CD44 protein expression. Immunoblotting and immunofluorescence revealed the GM35 Ag to be an apically expressed v6 variant exon-containing form of human CD44 (CD44v6). ELISA analysis demonstrated the release of soluble CD44v6 by T84 cells during PMN transepithelial migration. In addition, the observed release of CD44v6 was blocked by GM35 treatment, supporting a connection between CD44v6 release and PMN detachment. Increased expression of CD44v6 and the GM35 Ag was detected in inflamed ulcerative colitis tissue. This study demonstrates that epithelial-expressed CD44v6 plays a role in PMN clearance during inflammatory episodes through regulation of the terminal detachment of PMNs from the apical epithelial surface into the lumen of the intestine.
STAT1-Activating Cytokines Limit Th17 Responses through Both T-bet–Dependent and –Independent Mechanisms
Authors: Villarino Alejandro V. , Gallo Eugenio , Abbas Abul K.
Published: October 2010

Given the association with autoimmune disease, there is great interest in defining cellular factors that limit overactive or misdirected Th17-type inflammation. Using in vivo and in vitro models, we investigated the molecular mechanisms for cytokine-mediated inhibition of Th17 responses, focusing on the role of STAT1 and T-bet in this process. These studies demonstrate that, during systemic inflammation, STAT1- and T-bet–deficient T cells each exhibit a hyper-Th17 phenotype relative to wild-type controls. However, IL-17 production was greater in the absence of T-bet, and when both STAT1 and T-bet were deleted, there was no further increase, with the double-deficient cells instead behaving more like STAT1-deficient counterparts. Similar trends were observed during in vitro priming, with production of Th17-type cytokines greater in T-bet−/− T cells than in either STAT1−/− or STAT1−/− T-bet−/− counterparts. The ability of IFN-γ and IL-27 to suppress Th17 responses was reduced in T-bet–deficient cells, and most importantly, ectopic T-bet could suppress signature Th17 gene products, including IL-17A, IL-17F, IL-22, and retinoic acid-related orphan receptor γT, even in STAT1-deficient T cells. Taken together, these studies formally establish that, downstream of IFN-γ, IL-27, and likely all STAT1-activating cytokines, there are both STAT1 and T-bet–dependent pathways capable of suppressing Th17 responses.
The Chlamydia muridarum-Induced IFN-β Response Is TLR3-Dependent in Murine Oviduct Epithelial Cells
Authors: Derbigny Wilbert A. , Johnson Raymond M. , Toomey Katherine S. , Ofner Susan , Jayarapu Krupakar
Published: October 2010

Epithelial cells lining the murine genital tract act as sentinels for microbial infection, play a major role in the initiation of the early inflammatory response, and can secrete factors that modulate the adaptive immune response when infected with Chlamydia. C. muridarum-infected murine oviduct epithelial cells secrete the inflammatory cytokines IL-6 and GM-CSF in a TLR2-dependent manner. Further, C. muridarum infection induces IFN-β synthesis in the oviduct epithelial cells in a TRIF-dependent manner. Because murine oviduct epithelial cells express TLR3 but not TLRs 4, 7, 8, or 9, we hypothesized that TLR3 or an unknown TRIF-dependent pattern recognition receptor was the critical receptor for IFN-β production. To investigate the role of TLR3 in the Chlamydia-induced IFN-β response in oviduct epithelial cells, we used small interfering RNA, dominant-negative TLR3 mutants, and TLR3-deficient oviduct epithelial cells to show that the IFN-β secreted during C. muridarum infection requires a functional TLR3. Interestingly, we demonstrate that the TLR3 signaling pathway is not required for IFN-β synthesis in C. muridarum-infected macrophages, suggesting that there are alternate and redundant pathways to Chlamydia-induced IFN-β synthesis that seem to be dependent upon the cell type infected. Finally, because there is no obvious dsRNA molecule associated with Chlamydia infection, the requirement for TLR3 in Chlamydia-induced IFN-β synthesis in infected oviduct epithelial cells implicates a novel ligand that binds to and signals through TLR3.
Unexpected Role for the B Cell-Specific Src Family Kinase B Lymphoid Kinase in the Development of IL-17–Producing γδ T Cells
Authors: Laird Renee M. , Laky Karen , Hayes Sandra M.
Published: October 2010

The Ag receptors on αβ and γδ T cells differ not only in the nature of the ligands that they recognize but also in their signaling potential. We hypothesized that the differences in αβ- and γδTCR signal transduction were due to differences in the intracellular signaling pathways coupled to these two TCRs. To investigate this, we used transcriptional profiling to identify genes encoding signaling molecules that are differentially expressed in mature αβ and γδ T cell populations. Unexpectedly, we found that B lymphoid kinase (Blk), a Src family kinase expressed primarily in B cells, is expressed in γδ T cells but not in αβ T cells. Analysis of Blk-deficient mice revealed that Blk is required for the development of IL-17–producing γδ T cells. Furthermore, Blk is expressed in lymphoid precursors and, in this capacity, plays a role in regulating thymus cellularity during ontogeny.
Phases 1–3 Clinical Trials Using Adult Stem Cells in Osteonecrosis and Nonunion Fractures
Authors: Hauzeur Jean-Philippe , Gangji Valérie
Published: October 2010

Nonunion fractures and aseptic bone necrosis are two pathological conditions having some impairment of the cellular part of the repair: a reduction of MSC and of the osteoblastic activation. Both are good candidates for cell-based therapies using stem cells. We made a review of the published human trials. Only autologous bone marrow aspirate implantation was until now used. In Nonunion, a direct injection—15 to 150 ml—was made in 4 case series studies. In another, the bone marrow aspirate was concentrated before injection. The results were good. In bone necrosis, only one level 1 study was published. The results at 24 months were positive in terms of reduction of the necrosis and appearance of collapse. In 3 case series studies, a treatment with concentrated bone marrow aspirates was deemed useful with good results in 76 to 96%. These results are interesting but need confirmation by controlled studies.
Optimal Production Control in Stochastic Manufacturing Systems with Degenerate Demand
Authors: Baten Azizul , Kamil Anton Abdulbasah
Published: October 2010

The paper studies the production inventory problem of minimizing the expected discounted present value of production cost control in manufacturing systems with degenerate stochastic demand. We have developed the optimal inventory production control problem by deriving the dynamics of the inventory-demand ratio that evolves according to a stochastic neoclassical differential equation through Ito's Lemma. We have also established the Riccati based solution of the reduced (one- dimensional) HJB equation corresponding to production inventory control problem through the technique of dynamic programming principle. Finally, the optimal control is shown to exist from the optimality conditions in the HJB equation.
Toward continuous monitoring of seawater 13CO2/12CO2 isotope ratio and pCO2: Performance of cavity ringdown spectroscopy and gas matrix effects
Authors: Friedrichs Gernot , Bock Julia , Temps Friedrich , Fietzek Peer , Körtzinger Arne , Wallace Douglas W. R.
Published: October 2010

The potential of a continuous wave cavity ringdown spectrometer for monitoring the isotope ratio 13CO2/12CO2 and the partial pressure pCO2 of CO2 dissolved in water was thoroughly analyzed by quantitative measurements. Running calibration gas standards under typical operation conditions, a relative accuracy of Δ(δ13C[CO2]) = ±0.1‰ with 120 min averaging time has been demonstrated. Absolute uncertainties were determined to be Δ(δ13C[CO2]) = ±0.2‰ and Δ(xCO2) = ±0.5 ppmv. No principle problems were encountered when using the instrument in combination with a water‐air equilibration setup. By contrast, when performing measurements of CO2 in gas matrices with a composition different from that of ambient air, pressure broadening linewidth effects induced significant errors in both δ13C(CO2) and xCO2 values. These effects, which compromise the accessible accuracy in environmental studies, can be quantitatively taken into account by using a spectroscopically based correction procedure. Relying on linewidth analysis, the instrument was shown to be capable of continuous and simultaneous measurement of δ13C(CO2), pCO2, as well as water content and O2 supersaturation, and thus holds the potential for online monitoring of these quantities aboard research vessels.