bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultralow-Power SOTB CMOS Technology Operating Down to 0.4 V
Authors: Sugii Nobuyuki , Yamamoto Yoshiki , Makiyama Hideki , Yamashita Tomohiro , Oda Hidekazu , Kamohara Shiro , Yamaguchi Yasuo , Ishibashi Koichiro , Mizutani Tomoko , Hiramoto Toshiro
Published: April 2014

Ultralow-voltage (ULV) CMOS will be a core building block of highly energy efficient electronics. Although the operation at the minimum energy point (MEP) is effective for ULP CMOS circuits, its slow operation speed often means that it is not used in many applications. The silicon-on-thin-buried-oxide (SOTB) CMOS is a strong candidate for the ultralow-power (ULP) electronics because of its small variability and back-bias control. Proper power and performance optimization with adaptive Vth control taking advantage of SOTB’s features can achieve the ULP operation with acceptably high speed and low leakage. This paper describes our results on the ULV operation of logic circuits (CPU, SRAM, ring oscillator and other logic circuits) and shows that the operation speed is now sufficiently high for many ULP applications. The “Perpetuum-Mobile” micro-controllers operating down to 0.4 V or lower are expected to be implemented in a huge number of electronic devices in the internet-of-things (IoT) era.
Graphite and Hybrid Nanomaterials as Lubricant Additives
Authors: Zhang Zhenyu , Simionesie Dorin , Schaschke Carl
Published: April 2014

Lubricant additives, based on inorganic nanoparticles coated with organic outer layer, can reduce wear and increase load-carrying capacity of base oil remarkably, indicating the great potential of hybrid nanoparticles as anti-wear and extreme-pressure additives with excellent levels of performance. The organic part in the hybrid materials improves their flexibility and stability, while the inorganic part is responsible for hardness. The relationship between the design parameters of the organic coatings, such as molecular architecture and the lubrication performance, however, remains to be fully elucidated. A survey of current understanding of hybrid nanoparticles as lubricant additives is presented in this review.
Effect of High Pressure Microfluidization on the Crystallization Behavior of Palm Stearin — Palm Olein Blends
Authors: Han Lijuan , Li Lin , Li Bing , Zhao Lei , Liu Guoqin , Liu Xinqi , Wang Xuede
Published: April 2014

Moderate and high microfluidization pressures (60 and 120 MPa) and different treatment times (once and twice) were used to investigate the effect of high-pressure microfluidization (HPM) treatment on the crystallization behavior and physical properties of binary mixtures of palm stearin (PS) and palm olein (PO). The polarized light microscopy (PLM), texture analyzer, X-ray diffraction (XRD) and differential scanning calorimetry (DSC) techniques were applied to analyze the changes in crystal network structure, hardness, polymorphism and thermal property of the control and treated blends. PLM results showed that HPM caused significant reductions in maximum crystal diameter in all treated blends, and thus led to changes in the crystal network structure, and finally caused higher hardness in than the control blends. The XRD study demonstrated that HPM altered crystalline polymorphism. The HPM-treated blends showed a predominance of the more stable β' form, which is of more interest for food applications, while the control blend had more α- and β-form. This result was further confirmed by DSC observations. These changes in crystallization behavior indicated that HPM treatment was more likely to modify the crystallization processes and nucleation mechanisms.
Antioxidant and Antiproliferative Activities of Methanolic Extract from a Neglected Agricultural Product: Corn Cobs
Authors: Melo-Silveira Raniere , Fidelis Gabriel , Viana Rony , Soeiro Vinícius , Silva Rodrigo , Machado Daisy , Costa Leandro , Ferreira Carmen , Oliveira Rocha Hugo
Published: April 2014

Neglected agricultural products (NAPs) are defined as discarded material in agricultural production. Corn cobs are a major waste of agriculture maize. Here, a methanolic extract from corn cobs (MEC) was obtained. MEC contains phenolic compounds, protein, carbohydrates (1.4:0.001:0.001). We evaluated the in vitro and in vivo antioxidant potential of MEC. Furthermore, its antiproliferative property against tumor cells was assessed through MTT assays and proteins related to apoptosis in tumor cells were examined by western blot. MEC showed no hydroxyl radical scavenger capacity, but it showed antioxidant activity in Total Antioxidant Capacity and DPPH scavenger ability assays. MEC showed higher Reducing Power than ascorbic acid and exhibited high Superoxide Scavenging activity. In tumor cell culture, MEC increased catalase, metallothionein and superoxide dismutase expression in accordance with the antioxidant tests. In vivo antioxidant test, MEC restored SOD and CAT, decreased malondialdehyde activities and showed high Trolox Equivalent Antioxidant Capacity in animals treated with CCl4. Furthermore, MEC decreased HeLa cells viability by apoptosis due an increase of Bax/Bcl-2 ratio, caspase 3 active. Protein kinase C expression increased was also detected in treated tumor cells. Thus, our findings pointed out the biotechnological potential of corn cobs as a source of molecules with pharmacological activity.
Conformational Characterization of Ipomotaosides and Their Recognition by COX-1 and 2
Authors: Arantes Pablo , Sachett Liana , Graebin Cedric , Verli Hugo
Published: April 2014

The aerial parts of Ipomoea batatas are described herein to produce four new resin glycosides, designated as ipomotaosides A, B, C, and D. Ipomotaoside A was found to present inhibitory activity on both cyclooxygenases. However, the conformational elucidation of these molecules may be difficult due to their high flexibility. In this context, the current work presents a conformational characterization of ipomotaosides A–D in aqueous and nonaqueous solvents. The employed protocol includes metadynamics evaluation and unrestrained molecular dynamics simulations (MD). The obtained data provided structural models for the ipomotaosides in good agreement with previous ROESY distances measured in pyridine. Accordingly, the most abundant conformation of ipomotaoside A in solution was employed in flexible docking studies, providing a structural basis for the compound’s inhibition of COX enzymes. The so-obtained complex supports resin glycosides’ role as original scaffolds for future studies, aiming at structural optimization and development of potential new anti-inflammatory agents.
Ascorbic Acid and the Brain: Rationale for the Use against Cognitive Decline
Authors: Harrison Fiona , Bowman Gene , Polidori Maria
Published: April 2014

This review is focused upon the role of ascorbic acid (AA, vitamin C) in the promotion of healthy brain aging. Particular attention is attributed to the biochemistry and neuronal metabolism interface, transport across tissues, animal models that are useful for this area of research, and the human studies that implicate AA in the continuum between normal cognitive aging and age-related cognitive decline up to Alzheimer’s disease. Vascular risk factors and comorbidity relationships with cognitive decline and AA are discussed to facilitate strategies for advancing AA research in the area of brain health and neurodegeneration.
The Almost Periodic Rigidity of Crystallographic Bar-Joint Frameworks
Authors: Badri Ghada , Kitson Derek , Power Stephen
Published: April 2014

A crystallographic bar-joint framework, C in Rd, is shown to be almost periodically infinitesimally rigid if and only if it is strictly periodically infinitesimally rigid and the rigid unit mode (RUM) spectrum, Ω (C), is a singleton. Moreover, the almost periodic infinitesimal flexes of C are characterised in terms of a matrix-valued function, ΦC(z), on the d-torus, Td, determined by a full rank translation symmetry group and an associated motif of joints and bars.
Perioperative Chemotherapy for Gastroesophageal Cancer in British Columbia: A Multicentre Experience
Authors: Peixoto R.D. , Cheung W.Y. , Lim H.J.
Published: April 2014

Background: In 2006, perioperative epirubicin, cisplatin, and 5-fluorouracil (ECF), compared with surgery alone, demonstrated a significant survival benefit in resectable gastroesophageal cancers. We report the results of our experience with that protocol. Methods: The BC Cancer Agency (BCAA) is a multicentre institution that treats most oncology patients for the province. Characteristics of the 83 bcca patients with localized gastric, gastroesophageal junction, or lower esophageal cancer who initiated perioperative chemotherapy either ecf or epirubicin, cisplatin, and capecitabine (ECX) from 2008 to 2011 were abstracted to an anonymous database and analyzed. Results: Of the 83 patients in the cohort [66 men; median age: 62 years (range: 37–79 years)], 87.9% completed 3 cycles of perioperative chemotherapy, and 93.9% (n = 78) underwent an attempt at surgery (2 patients died of chemotherapy toxicities, 1 refused surgery, and 2 developed disease progression before surgery). In 11 of the surgeries (14.1%), tumours could not be resected because of unresectability (n = 1), liver metastasis (n = 1), and peritoneal carcinomatosis (n = 9). One patient died of surgical complications. The 6 patients (7.2%) who achieved a pathologic complete response are all alive and recurrence-free. Of 46 patients (55.4%) who subsequently began postoperative chemotherapy, 44.5% completed 3 cycles. Estimated median survival was 40.3 months. Weight loss was the only significant prognostic factor for worse overall survival. Conclusions: Our multicentre experience confirmed the feasibility of the MAGIC protocol in a real-world scenario and showed that ECX is also an adequate regimen in the perioperative setting. Weight loss was the only significant prognostic factor for worse overall survival. All patients who achieved a pathologic complete response are recurrence-free after a median followup of 40.3 months.
PREDICTION OF DEFAULT PROBABILITY FOR CONSTRUCTION FIRMS USING THE LOGIT MODEL
Authors: Tserng H. Ping , Chen Po-Cheng , Huang Wen-Haw , Lei Man Cheng , Tran Quang Hung
Published: April 2014

Recently, the high incidence of construction firm bankruptcies has underlined the importance of forecasting defaults in the construction industry. Early warning systems need to be developed to prevent or avert contractor default; additionally, this evaluation result could facilitate the selection of firms as collaboration or investment partners. Financial statements are considered one of the key basic evaluation tools for demonstrating firm strength. This investigation provides a framework for assessing the probability of construction contractor default based on financial ratios by using the Logit model. A total of 21 ratios, gathered into five financial groups, are utilized to perform univariate logit analysis and multivariate logit analysis for assessing contractor default probability. The empirical results indicate that using multivariate analysis by adding market factor to the liquidity, leverage, activity and profitability factors can increase the accuracy of default prediction more than using only four financial factors. While considering the market factor in the multivariate Logit model, clear incremental prediction performance appears in 1-year evaluation. This study thus suggests that the market factor comprises important information to increase the prediction performance of the model when applied to construction contractors, particularly in short-term evaluation.
EVALUATION OF GROOVING METHOD TO POSTPONE DEBONDING OF FRP LAMINATES IN WPC-FRP BEAMS
Authors: Arefi Shahin Lale , Naghipour Morteza , Turskis Zenonas , Nematzadeh Mehdi
Published: April 2014

The use of lightweight construction material with high corrosion resistance and low cost plays an important role in the design and construction of marine structures such as waterfronts. One of the most common methods for strengthening the structures is composite fibre reinforced plastic (FRP) sheet that is used for member retrofitting including wood plastic composite (WPC). The WPC material is produced from wood and compressed resin, which has good mechanical properties as well as economic benefits. The main problem of WPC reinforced with FRP sheets is the debonding of the sheet from WPC surface, which leads to premature and non-economic failure in members. One of the existing methods to solve this problem is surface preparation. However, surface preparation of wood plastic composite has some additional problems, such as operational cost, environmental pollution, etc. Therefore, to avoid debonding, another method has been used, known as the grooving method at the lower parts of beams. The laboratory used 50 I-shaped specimens with the same geometrical and mechanical properties. Initially, some slots such as longitudinal, transverse and diagonal grooves were created on the surface of specimens and filled by an epoxy. All beams were armed using one or two layers of GFRP sheets embedded at the lower part and were tested under four-point flexural loading. Grooves of different shapes, various widths and depths as well as the number of reinforcement layers were determined for considering their effect on the beam's behaviour. The results expressed that the debonding of FRP sheets can be delayed by selecting the longitudinal grooves with certain width and depth, which also leads to resistance improvement.
UPGRADING THE OLD VERNACULAR BUILDING TO CONTEMPORARY NORMS: MULTIPLE CRITERIA APPROACH
Authors: Šiožinytė Eglė , Antuchevičienė Jurgita , Kutut Vladislavas
Published: April 2014

Sustainable development is emphasized in the process of construction or modernization of buildings at present. Old vernacular architecture does not satisfy contemporary building norms such as daylighting and/or thermal performance parameters. These parameters are important for sustainability due to their relation with energy savings. It is obvious that seeking to improve these parameters, old buildings should be upgraded. The main problem is how to reach contemporary building norms without a negative impact to architectural heritage in a process of modernisation. The aim of the research is to find the best compromise solution for effective vernacular architecture's change. The Authors suggest using multiple criteria approach that enables to evaluate possible alternative solutions in several controversial aspects and to find rational building's modernisation type. Also, suitability of combination of usual MCDM (Multiple Criteria Decision Making) methods with grey systems theory due to possibility of processing of large quantity of uncertain information is highlighted in the research. TOPSIS Grey (Technique for Order Preference by Similarity to Ideal Solution with grey numbers) and AHP (Analytic Hierarchy Process) methods are applied for the presented case study of upgrading the old vernacular building. Taking into account multiple quantitative and qualitative criteria and experts' opinion, the rational vernacular building's modernisation variant is chosen. Based on the comprehensive analysis, research conclusions and recommendations are formulated.
RECOVERING EEG SIGNALS: MUSCLE ARTIFACT SUPPRESSION USING WAVELET-ENHANCED, INDEPENDENT COMPONENT ANALYSIS INTEGRATED WITH ADAPTIVE FILTER
Authors: Chiu Chuang-Chien , Hai Bui Huy , Yeh Shoou-Jeng , Liao Ken Ying-Kai
Published: April 2014

Independent component analysis (ICA) has been proven to be a powerful tool for removing artifacts from electroencephalogram (EEG) recordings in the form of blind source separation (BSS). Independent components (ICs) come from undesired sources that are mixed with the useful signal, and the assessment of such ICs allows them to be detected. But the unwanted ICs also can contain some useful information. To overcome this problem, wavelet-enhanced ICA (wICA) can be used, and this method applies a wavelet threshold for each wavelet coefficient to suppress abnormal deformation in each wavelet coefficient. Using the wICA algorithm to suppress artifacts provides an EEG signal with less distortion in the amplitude and in the phase of the cerebral part of the EEG, and the cerebral part of the EEG can be estimated and obtained very similar to control conditions. However, the EEG signals are affected by various artifact components, and those that have the greatest influence are electromyography (EMG) and electrooculography (EOG). These artifacts may appear simultaneously, randomly or interruptedly, so a fixed threshold level is not really appropriate. We proposed a system including wICA integrated with an adaptive filter model, and this combination system can provide the best prediction of the impacts of artifacts to set up a threshold value that is adaptive and suitable. Our experimental results showed that are approach provided better rejection of artifacts than the wICA system.
Identity-Based Encryption Protocol for Privacy and Authentication in Wireless Networks
Authors: Mulkey Clifton , Kar Dulal C.
Published: April 2014

Wireless networks are inherently insecure due to the fact that information on the network can be passively retrieved by an eavesdropper using off-the-shelf network hardware and free software applications. The most common solution for this vulnerability is the Wireless Protected Access (WPA) protocol. This protocol provides data encryption and access control for wireless networks. However, the WPA protocol contains drawbacks in its authentication mechanisms that can cause inconveniences for end users and performance degradation for the network. Furthermore, many of the authentication methods used with WPA are not friendly to small and resource-constrained wireless devices. This chapter presents the design of a new wireless security protocol for privacy and authentication using efficient Identity-Based Encryption (IBE) techniques. This protocol can be used to eliminate the need for a central authentication server for enterprise networks, as well as to provide the new feature of privacy without authentication for public wireless networks. This work also puts forth an analysis and validation of the new protocol, including security strength, storage overhead, communication overhead, and computational efficiency.
Scientific Operations Combining ROV and AUV in the Trondheim Fjord
Authors: Martin Ludvigsen  , Johnsen Geir , Sørensen Asgeir J. , Lågstad Petter A. , Ødegård Øyvind
Published: April 2014

AbstractThis paper describes an autonomous underwater vehicle (AUV) and a remotely operated vehicle (ROV) complementing each other on a scientific cruise in the Trondheim Fjord (Norway). The Norwegian University of Science and Technology Applied Underwater Robotics-Laboratory and the Norwegian Defense Research Establishment mobilized for a collaborative cruise with an ROV equipped with video camera, dynamic positioning system, still camera for photographic mosaic, underwater hyperspectral imager (UHI) and inertial measurement unit, and the AUVHugin HUSwith synthetic aperture sonar (SAS) and still camera as main instruments. A multidisciplinary approach was used to set up the operations for using ROV, AUV, SAS, and UHI to document archaeological and biological sites. The cruise was run as an integrated operation processing data online and using collected data actively in the cruise planning and replanning.The AUV presented unparalleled area coverage capacity for mapping and search, while the ROV provided detailed information from the sites. During the cruise, approximately 20 km2were mapped with high-resolution sensors, and the data were ground-truthed using the ROV. These data provided new information and insight of both biological and archaeological sites.
Design of Marine Structures Through Morphing Method and Its Supporting Techniques
Authors: Kang Ju Young
Published: April 2014

AbstractExternal forms of marine structures directly influence their performance. Therefore, it is important that their shapes are optimized in the design process. Modern design optimization techniques often require fast evaluation of large number of design alternatives,
and morphing techniques have the ability to generate a large number of designs on demand. Morphing is a geometric interpolation technique that changes one object into another and is capable of creating an infinite number of intermediate forms from parent models. This paper discusses the application
of a morphing technique for rapid generation of marine structures. In addition, the paper presents several supporting techniques for addressing some of the problems associated with morphing. It has been found that the morphing technique is a useful additional tool for product design optimization.
Impact of Asymptomatic Herpes Simplex Virus Type 2 Infection on Mucosal Homing and Immune Cell Subsets in the Blood and Female Genital Tract
Authors: Shannon Brett , Yi Tae Joon , Thomas-Pavanel Jamie , Chieza Lisungu , Janakiram Praseedha , Saunders Megan , Tharao Wangari , Huibner Sanja , Remis Robert , Rebbapragada Anu , Kaul Rupert
Published: April 2014

HSV-2 infection is common and generally asymptomatic, but it is associated with increased HIV susceptibility and disease progression. This may relate to herpes-mediated changes in genital and systemic immunology. Cervical cytobrushes and blood were collected from HIV-uninfected African/Caribbean women in Toronto, and immune cell subsets were enumerated blindly by flow cytometry. Immune differences between groups were assessed by univariate analysis and confirmed using a multivariate model. Study participants consisted of 46 women, of whom 54% were infected with HSV-2. T cell activation and expression of the mucosal homing integrin α4β7 (19.60 versus 8.76%; p < 0.001) were increased in the blood of HSV-2–infected women. Furthermore, expression of α4β7 on blood T cells correlated with increased numbers of activated (coexpressing CD38/HLA-DR; p = 0.004) and CCR5+ (p = 0.005) cervical CD4+ T cells. HSV-2–infected women exhibited an increase in the number of cervical CD4+ T cells (715 versus 262 cells/cytobrush; p = 0.016), as well as an increase in the number and proportion of cervical CD4+ T cells that expressed CCR5+ (406 versus 131 cells, p = 0.001; and 50.70 versus 34.90%, p = 0.004) and were activated (112 versus 13 cells, p < 0.001; and 9.84 versus 4.86%, p = 0.009). Mannose receptor expression also was increased on cervical dendritic cell subsets. In conclusion, asymptomatic HSV-2 infection was associated with significant systemic and genital immune changes, including increased immune activation and systemic α4β7 expression; correlation of the latter with highly HIV-susceptible CD4+ T cell subsets in the cervix may provide a mechanism for the increased HIV susceptibility observed in asymptomatic HSV-2–infected women.
TLR3 Activation Augments Matrix Metalloproteinase Production through Reactive Nitrogen Species Generation in Human Lung Fibroblasts
Authors: Ichikawa Tomohiro , Sugiura Hisatoshi , Koarai Akira , Minakata Yoshiaki , Kikuchi Takashi , Morishita Yukiko , Oka Asako , Kanai Kuninobu , Kawabata Hiroki , Hiramatsu Masataka , Akamatsu Keiichiro , Hirano Tsunahiko , Nakanishi Masanori , Matsunaga Kazuto , Yamamoto Nobuyuki , Ichinose Masakazu
Published: April 2014

Viral infection often triggers asthma exacerbation and contributes to airway remodeling. Cell signaling in viral infection is mainly mediated through TLR3. Many mediators are involved in airway remodeling, but matrix metalloproteinases (MMPs) are key players in this process in asthma. However, the role of TLR3 activation in production of MMPs is unknown. In this study, we examined the effects of polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3, on production of MMPs in human lung fibroblasts, with a focus on nitrosative stress in TLR3 modulation of MMP production. After lung fibroblasts were treated with poly(I:C), production of MMP-1, -2, and -9 and inducible NO synthase (iNOS) was assessed. The roles of NF-κB and IFN regulatory factor-3 (IRF-3) in the poly(I:C)-mediated production of MMPs and the responsiveness to poly(I:C) of normal lung fibroblasts and asthmatic lung fibroblasts were also investigated. Poly(I:C) augmented production of MMPs and iNOS in fibroblasts, and an iNOS inhibitor diminished this production of MMPs. Poly(I:C) stimulated translocation of NF-κB and IRF-3 into the nucleus in fibroblasts and inhibition of NF-κB or IRF-3 abrogated the poly(I:C)-induced increase in both iNOS expression and release of MMPs. Poly(I:C)-induced production of iNOS and MMPs was greater in asthmatic fibroblasts than in normal fibroblasts. We conclude that viral infection may induce nitrosative stress and subsequent MMP production via NF-κB– and IRF-3–dependent pathways, thus potentiating viral-induced airway remodeling in asthmatic airways.
Ezh2 Regulates Transcriptional and Posttranslational Expression of T-bet and Promotes Th1 Cell Responses Mediating Aplastic Anemia in Mice
Authors: Tong Qing , He Shan , Xie Fang , Mochizuki Kazuhiro , Liu Yongnian , Mochizuki Izumi , Meng Lijun , Sun Hongxing , Zhang Yanyun , Guo Yajun , Hexner Elizabeth , Zhang Yi
Published: April 2014

Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome. IFN-γ–producing Th1 CD4+ T cells mediate the immune destruction of hematopoietic cells, and they are central to the pathogenesis. However, the molecular events that control the development of BM-destructive Th1 cells remain largely unknown. Ezh2 is a chromatin-modifying enzyme that regulates multiple cellular processes primarily by silencing gene expression. We recently reported that Ezh2 is crucial for inflammatory T cell responses after allogeneic BM transplantation. To elucidate whether Ezh2 mediates pathogenic Th1 responses in AA and the mechanism of Ezh2 action in regulating Th1 cells, we studied the effects of Ezh2 inhibition in CD4+ T cells using a mouse model of human AA. Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure. Ezh2 inhibition resulted in significant decrease in the expression of Tbx21 and Stat4, which encode transcription factors T-bet and STAT4, respectively. Introduction of T-bet but not STAT4 into Ezh2-deficient T cells fully rescued their differentiation into Th1 cells mediating AA. Ezh2 bound to the Tbx21 promoter in Th1 cells and directly activated Tbx21 transcription. Unexpectedly, Ezh2 was also required to prevent proteasome-mediated degradation of T-bet protein in Th1 cells. Our results demonstrate that Ezh2 promotes the generation of BM-destructive Th1 cells through a mechanism of transcriptional and posttranscriptional regulation of T-bet. These results also highlight the therapeutic potential of Ezh2 inhibition in reducing AA and other autoimmune diseases.
Transient Systemic Inflammation Does Not Alter the Induction of Tolerance to Gastric Autoantigens by Migratory Dendritic Cells
Authors: Bourges Dorothée , Ross Ellen M. , Allen Stacey , Read Simon , Houghton Fiona J. , Bedoui Sammy , Boon Louis , Gleeson Paul A. , van Driel Ian R.
Published: April 2014

It has been proposed that activation of dendritic cells (DCs) presenting self-antigens during inflammation may lead to activation of autoreactive T cells and the development of autoimmunity. To test this hypothesis, we examined the presentation of the autoantigen recognized in autoimmune gastritis, gastric H+/K+ ATPase, which is naturally expressed in the stomach and is constitutively presented in the stomach-draining lymph nodes. Systemic administration to mice of the TLR9 agonist CpG DNA, agonist anti-CD40 Ab, or TLR4 agonist LPS all failed to abrogate the process of peripheral clonal deletion of H+/K+ ATPase–specific CD4 T cells or promote the development of autoimmune gastritis. We demonstrated that migratory DCs from the stomach-draining lymph nodes are the only DC subset capable of constitutively presenting the endogenous gastric H+/K+ ATPase autoantigen in its normal physiological context. Analysis of costimulatory molecules indicated that, relative to resident DCs, migratory DCs displayed a partially activated phenotype in the steady state. Furthermore, migratory DCs were refractory to stimulation by transient exposure to TLR agonists, as they failed to upregulate costimulatory molecules, secrete significant amounts of inflammatory cytokines, or induce differentiation of effector T cells. Together, these data show that transient systemic inflammation failed to break tolerance to the gastric autoantigen, as migratory DCs presenting the gastric autoantigen remain tolerogenic under such conditions, demonstrating the robust nature of peripheral tolerance.
Acute-Phase Protein α1-Antitrypsin—A Novel Regulator of Angiopoietin-like Protein 4 Transcription and Secretion
Authors: Frenzel Eileen , Wrenger Sabine , Immenschuh Stephan , Koczulla Rembert , Mahadeva Ravi , Deeg H. Joachim , Dinarello Charles A. , Welte Tobias , Marcondes A. Mario Q. , Janciauskiene Sabina
Published: April 2014

The angiopoietin-like protein 4 (angptl4, also known as peroxisome proliferator–activated receptor [PPAR]γ–induced angiopoietin-related protein) is a multifunctional protein associated with acute-phase response. The mechanisms accounting for the increase in angptl4 expression are largely unknown. This study shows that human α1-antitrypsin (A1AT) upregulates expression and release of angplt4 in human blood adherent mononuclear cells and in primary human lung microvascular endothelial cells in a concentration- and time-dependent manner. Mononuclear cells treated for 1 h with A1AT (from 0.1 to 4 mg/ml) increased mRNA of angptl4 from 2- to 174-fold, respectively, relative to controls. In endothelial cells, the maximal effect on angptl4 expression was achieved at 8 h with 2 mg/ml A1AT (11-fold induction versus controls). In 10 emphysema patients receiving A1AT therapy (Prolastin), plasma angptl4 levels were higher relative to patients without therapy (nanograms per milliliter, mean [95% confidence interval] 127.1 [99.5–154.6] versus 76.8 [54.8–98.8], respectively, p = 0.045) and correlated with A1AT levels. The effect of A1AT on angptl4 expression was significantly diminished in cells pretreated with a specific inhibitor of ERK1/2 activation (UO126), irreversible and selective PPARγ antagonist (GW9662), or genistein, a ligand for PPARγ. GW9662 did not alter the ability of A1AT to induce ERK1/2 phosphorylation, suggesting that PPARγ is a critical mediator in the A1AT-driven angptl4 expression. In contrast, the forced accumulation of HIF-1α, an upregulator of angptl4 expression, enhanced the effect of A1AT. Thus, acute-phase protein A1AT is a physiological regulator of angptl4, another acute-phase protein.
Cutting Edge: T Cell Development Requires the Combined Activities of the p110γ and p110δ Catalytic Isoforms of Phosphatidylinositol 3-Kinase
Authors: Webb Louise M. C. , Vigorito Elena , Wymann Matthias P. , Hirsch Emilio , Turner Martin
Published: April 2014

The role of PI3K activity in T lymphocyte development is obscure because mice deficient in single PI3K catalytic subunits either die before birth (p110α−/− and p110β−/−) or lack a significant T cell developmental phenotype (p110γ−/− and p110δ−/−). We have generated mice deficient in both p110γ and p110δ and show that p110γ/δ−/− mice have a profound block in T cell development that occurs at the β-selection checkpoint. We show that pre-TCR-induced signaling is significantly reduced in p110γ/δ−/− thymocytes and that this results in a concomitant lack of proliferative expansion and increased apoptosis. The survival defect in p110γ/δ−/− thymocytes is associated with increased levels of the pro-apoptotic molecule Bcl2 interacting mediator of cell death. This work demonstrates that PI3K activity is critical for T cell development and depends on the combined function of p110γ and p110δ.
Cutting Edge: Proangiogenic Properties of Alternatively Activated Dendritic Cells
Authors: Riboldi Elena , Musso Tiziana , Moroni Emanuela , Urbinati Chiara , Bernasconi Sergio , Rusnati Marco , Adorini Luciano , Presta Marco , Sozzani Silvano
Published: April 2014

Angiogenesis plays an important role in tissue remodeling and repair during the late phase of inflammation. In the present study, we show that human dendritic cells (DC) that matured in the presence of anti-inflammatory molecules such as calcitriol, PGE2, or IL-10 (alternatively activated DC) selectively secrete the potent angiogenic cytokine vascular endothelial growth factor (VEGF) isoforms VEGF165 and VEGF121. No VEGF production was observed in immature or classically activated DC. Also, the capacity to produce VEGF was restricted to the myeloid DC subset. When implanted in the chick embryo chorioallantoic membrane, alternatively activated DC elicit a marked angiogenic response, which is inhibited by neutralizing anti-VEGF Abs and by the VEGFR-2 inhibitor SU5416. Therefore, alternatively activated DC may contribute to the resolution of the inflammatory reaction by promoting VEGF-induced angiogenesis.
Secretory IgA Possesses Intrinsic Modulatory Properties Stimulating Mucosal and Systemic Immune Responses
Authors: Favre Laurent , Spertini François , Corthésy Blaise
Published: April 2014

Secretory IgA (SIgA) is essential in protecting mucosal surfaces by ensuring immune exclusion. In addition, SIgA binds selectively to M cells in Peyer’s patches (PP), resulting in transport across the epithelium and targeting of dendritic cells (DC) in the dome region. The immunological consequences of such an interaction are unknown. In this study, we find that oral delivery of SIgA comprising human secretory component and mouse IgA induces human secretory component-specific Ab and cellular responses in mucosal and peripheral tissues in mice. This takes place in the absence of coaddition of cholera toxin, identifying so far unraveled properties in SIgA. Specific immune responses are accompanied by sustained IL-10 and TGF-β expression in draining mesenteric lymph nodes and spleen. SIgA also triggers migration of DC to the T cell-rich regions of PP, and regulates expression of CD80 and CD86 on DC in PP, mesenteric lymph nodes, and spleen. These results provide evidence that mucosal SIgA re-entering the body exerts a function of Ag delivery that contributes to effector and/or regulatory pathways characteristic of the intestinal mucosal compartment.
B Cell Maturation Antigen, the Receptor for a Proliferation-Inducing Ligand and B Cell-Activating Factor of the TNF Family, Induces Antigen Presentation in B Cells
Authors: Yang Min , Hase Hidenori , Legarda-Addison Diana , Varughese Leena , Seed Brian , Ting Adrian T.
Published: April 2014

B cell maturation Ag (BCMA), a member of the TNFR superfamily expressed on B cells, binds to a proliferation-inducing ligand (APRIL) and B cell-activating factor of the TNF family (BAFF) but the specific B cell responses regulated by BCMA remain unclear. This study demonstrates that ligation of A20 B cells transfected with BCMA induces the expression of CD40, CD80/B7-1, CD86/B7-2, MHC class II, and CD54/ICAM-1, which subsequently enhances the presentation of OVA peptide Ag to DO11.10 T cells. BCMA expression in murine splenic B cells can be induced with IL-4 and IL-6, allowing subsequent treatment with APRIL or agonist anti-BCMA to similarly induce Ag presentation. A comparative analysis of hybrid receptors of TNFR2 fused to the cytoplasmic domains of APRIL/BAFF receptors found that only BCMA, but not transmembrane activator and calcium-modulator and cyclophilin ligand interactor or BAFF-R, is capable of activating Ag presentation. Although all three receptors can trigger NF-κB signaling, only BCMA activates the JNK pathway conferring on BCMA the specific ability to activate this Ag presentation response.
Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation
Authors: Yuan Rongwen , El-Asady Riham , Liu Kechang , Wang Donghua , Drachenberg Cinthia B. , Hadley Gregg A.
Published: April 2014

Immune destruction of the graft renal tubules is an important barrier to the long-term function of clinical renal allografts, but the underlying mechanisms remain obscure. CD103—an integrin conferring specificity for the epithelial cell-restricted ligand, E-cadherin—defines a subset of CD8 effectors that infiltrate the graft tubular epithelium during clinical rejection episodes, predicting a causal role for CD103+CD8+ effectors in tubular injury. In the present study, we used rodent transplant models to directly test this hypothesis. Surprisingly, CD8 cells infiltrating renal allografts undergoing unmodified acute rejection did not express significant levels of CD103. However, we demonstrate that a brief course of cyclosporine A to rat renal allograft recipients promotes progressive accumulation of CD103+CD8+ cells within the graft, concomitant with the development of tubular atrophy and interstitial fibrosis. As in the known clinical scenario, graft-associated CD103+CD8+ cells exhibited a T effector phenotype and were intimately associated with the renal tubular epithelium. Treatment with anti-CD103 mAb dramatically attenuated CD8 infiltration into the renal tubules and tubular injury. Mouse studies documented that CD103 expression is required for efficient destruction of the graft renal tubules by CD8 effectors directed to donor MHC I alloantigens. Taken together, these data document a causal role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation and identify novel targets for therapeutic intervention in this important clinical problem.
The Lyn Tyrosine Kinase Differentially Regulates Dendritic Cell Generation and Maturation
Authors: Chu Ching-Liang , Lowell Clifford A.
Published: April 2014

The Src family kinase Lyn plays both stimulatory and inhibitory roles in hemopoietic cells. In this report we provide evidence that Lyn is involved in dendritic cell (DC) generation and maturation. Loss of Lyn promoted DC expansion in vitro from bone marrow precursors due to enhanced generation and accelerated differentiation of Lyn-deficient DC progenitors. Differentiated Lyn-deficient DCs also had a higher survival rate. Similarly, the CD11c-positive cell number was increased in aged Lyn-deficient mice in vivo. In contrast to their enhanced generation, lyn−/− DCs failed to mature appropriately in response to innate stimuli, resulting in DCs with lower levels of MHC class II and costimulatory molecules. In addition, IL-12 production and Ag-specific T cell activation were reduced in lyn−/− DCs after maturation, resulting in impaired Th1 responses. This is the first study to characterize Lyn-deficient DCs. Our results suggest that Lyn kinase plays uniquely negative and positive regulatory roles in DC generation and maturation, respectively.
Minimal Contribution of Marrow-Derived Endothelial Precursors to Tumor Vasculature
Authors: Larrivée Bruno , Niessen Kyle , Pollet Ingrid , Corbel Stéphane Y. , Long Michael , Rossi Fabio M. , Olive Peggy L. , Karsan Aly
Published: April 2014

During embryogenesis, vascular and hemopoietic cells originate from a common precursor, the hemangioblast. Recent evidence suggests the existence of endothelial precursors in adult bone marrow cells, but it is unclear whether those precursors have a role in tumor neovascularization. In this report, we demonstrate that murine bone marrow contains endothelial progenitors, which arise from a cell with self-renewing capacity, and can integrate into tumor microvasculature, albeit at a very low frequency. A transgenic double-reporter strategy allowed us to demonstrate definitively that tumor bone marrow-derived endothelial cells arise by transdifferentiation of marrow progenitors rather than by cell fusion. Single cell transplants showed that a common precursor contributes to both the hemopoietic and endothelial lineages, thus demonstrating the presence of an adult hemangioblast. Furthermore, we demonstrate that increased vascular endothelial growth factor (VEGF)-A secretion by tumor cells, as well as activation of VEGF receptor-2 in bone marrow cells does not alter the mobilization and incorporation of marrow-derived endothelial progenitors into tumor vasculature. Finally, in human umbilical cord blood cells, we show that endothelial precursors make up only ∼1 in 107 mononuclear cells but are highly enriched in the CD133+ cell population. By ruling out cell fusion, we clearly demonstrate the existence of an adult hemangioblast, but the differentiation of marrow stem cells toward the endothelial lineage is an extremely rare event. Furthermore, we show that VEGF-A stimulation of hemopoietic cells does not significantly alter this process.
Alternative Mechanism by which IFN-γ Enhances Tumor Recognition: Active Release of Heat Shock Protein 72
Authors: Bausero Maria A. , Gastpar Robert , Multhoff Gabriele , Asea Alexzander
Published: April 2014

IFN-γ exhibits differential effects depending on the target and can induce cellular activation and enhance survival or mediate cell death via activation of apoptotic pathways. In this study, we demonstrate an alternative mechanism by which IFN-γ enhances tumor recognition, mediated by the active release of Hsp72. We demonstrate that stimulation of 4T1 breast adenocarcinoma cells and K562 erythroleukemic cells with IFN-γ triggers the cellular stress response, which results in the enhanced expression of total Hsp72 expression without a significant increase in cell death. Intracellular expression of Hsp72 was abrogated in cells stably transfected with a mutant hsf-1 gene. IFN-γ-induced Hsp72 expression correlated with enhanced surface expression and consequent release of Hsp72 into the culture medium. Pretreatment of tumors with compounds known to the block the classical protein transport pathway, including monensin, brefeldin A, tunicamycin, and thapsigargin, did not significantly block Hsp72 release. However, pretreatment with intracellular calcium chelator BAPTA-AM or disruption of lipid rafts using methyl β-cyclodextrin completely abrogated IFN-γ-induced Hsp72 release. Biochemical characterization revealed that Hsp72 is released within exosomes and has the ability to up-regulate CD83 expression and stimulate IL-12 release by naive dendritic cells. Pretreatment with neutralizing mAb or depletion of Hsp72 completely abrogated its chaperokine function. Taken together, these findings are indicative of an additional previously unknown mechanism by which IFN-γ promotes tumor surveillance and furthers our understanding of the central role of extracellular Hsp72 as an endogenous adjuvant and danger signal.
Sphingosine 1-Phosphate Receptors Regulate Chemokine-Driven Transendothelial Migration of Lymph Node but Not Splenic T Cells
Authors: Yopp Adam C. , Ochando Jordi C. , Mao Minwei , Ledgerwood Levi , Ding Yaozhong , Bromberg Jonathan S.
Published: April 2014

Chemokines and chemokine receptors are required for T cell trafficking and migration. Recent evidence shows that sphingosine 1-phosphate (S1P) and S1PRs are also important for some aspects of T cell migration, but how these two important receptor-ligand systems are integrated and coregulated is not known. In this study, we have investigated CCL19-CCR7 and CXCL12-CXCR4-driven migration of both splenic and peripheral lymph node (PLN) nonactivated and naive T cells, and used both S1P and the S1PR ligand, FTY720, to probe these interactions. The results demonstrate that splenic T cell migration to CCL19 or CXCL12 is enhanced by, but does not require, S1PR stimulation. In contrast, PLN T cell migration to CXCL12, but not CCL19, requires both chemokine and S1PR stimulation, and the requirement for dual receptor stimulation is particularly important for steps involving transendothelial migration. The results also demonstrate that: 1) splenic and PLN nonactivated and naive T cells use different molecular migration mechanisms; 2) CCR7 and CXCR4 stimulation engage different migration mechanisms; and 3) S1P and FTY720 have distinct S1PR agonist and antagonist properties. The results have important implications for understanding naive T cell entry into and egress from peripheral lymphoid organs, and we present a model for how S1P and chemokine receptor signaling may be integrated within a T cell.
The CD9 Tetraspanin Is Not Required for the Development of Peripheral B Cells or for Humoral Immunity
Authors: Cariappa Annaiah , Shoham Tsipi , Liu Haoyuan , Levy Shoshana , Boucheix Claude , Pillai Shiv
Published: April 2014

The CD9 tetraspanin is known to be expressed at high levels on marginal zone (MZ) B cells, B-1 B cells, and plasma cells, and its expression is believed to be dependent on signals derived via Btk. In CD9 null mice, however, the development and survival of MZ B cells, B-1 B cells, and plasma cells all appear to be unaffected, and humoral immune responses to T-dependent and T-independent Ags are similar to those seen in wild-type littermate controls. In wild-type mice, CD9 levels may serve to distinguish between the presumed MZ precursor B cell population in the spleen and other IgD-expressing transitional B cells that express lower levels of CD21 and CD1d. These results suggest that CD9 is dispensable for B cell development and humoral immunity, but that this protein may serve as an additional marker for the presumed MZ precursor population of splenic B cells.
CD4−8− Dendritic Cells Prime CD4+ T Regulatory 1 Cells to Suppress Antitumor Immunity
Authors: Zhang Xueshu , Huang Hui , Yuan Jinying , Sun Deming , Hou Wu-Shiun , Gordon John , Xiang Jim
Published: April 2014

It is clear that dendritic cells (DCs) are essential for priming of T cell responses against tumors. However, the distinct roles DC subsets play in regulation of T cell responses in vivo are largely undefined. In this study, we investigated the capacity of OVA-presenting CD4−8−, CD4+8−, or CD4−8+ DCs (OVA-pulsed DC (DCOVA)) in stimulation of OVA-specific T cell responses. Our data show that each DC subset stimulated proliferation of allogeneic and autologous OVA-specific CD4+ and CD8+ T cells in vitro, but that the CD4−8− DCs did so only weakly. Both CD4+8− and CD4−8+ DCOVA induced strong tumor-specific CD4+ Th1 responses and fully protective CD8+ CTL-mediated antitumor immunity, whereas CD4−8− DCOVA, which were less mature and secreted substantial TGF-β upon coculture with TCR-transgenic OT II CD4+ T cells, induced the development of IL-10-secreting CD4+ T regulatory 1 (Tr1) cells. Transfer of these Tr1 cells, but not T cells from cocultures of CD4−8− DCOVA and IL-10−/− OT II CD4+ T cells, into CD4−8+ DCOVA-immunized animals abrogated otherwise inevitable development of antitumor immunity. Taken together, CD4−8− DCs stimulate development of IL-10-secreting CD4+ Tr1 cells that mediated immune suppression, whereas both CD4+8− and CD4−8+ DCs effectively primed animals for protective CD8+ CTL-mediated antitumor immunity.