bluuebunny/crossref_metadata_2025_split huggingface dataset:
Follistatin-like Protein 1 and the Ferritin/Erythrocyte Sedimentation Rate Ratio Are Potential Biomarkers for Dysregulated Gene Expression and Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis
Authors: Gorelik Mark , Fall Ndate , Altaye Mekibib , Barnes Michael G. , Thompson Susan D. , Grom Alexei A. , Hirsch Raphael 
Published: May 2013

Objective.Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein overexpressed in certain inflammatory diseases. Our objective was to correlate FSTL-1 levels with gene expression, known biomarkers, and measures of disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS).Methods.FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, and 30 healthy controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin, and soluble interleukin-2 receptor-α (sIL-2Rα). Gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMC).Results.Serum levels of FSTL-1 were elevated at time of presentation of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p < 0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal following treatment (p < 0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Rα and ferritin. Ferritin/ESR ratio was superior to ferritin, sIL-2Rα, and FSTL-1 in discriminating MAS from new-onset sJIA. PBMC from patients with FSTL-1 levels > 200 ng/ml showed altered expression of genes related to innate immunity, erythropoiesis, and natural killer cell dysfunction. Two patients with the highest FSTL-1 levels at disease onset (> 300 ng/ml) ultimately developed MAS.Conclusion.Elevated pretreatment serum FSTL-1 levels in sJIA are associated with dysregulated gene expression suggestive of occult MAS, and may have utility in predicting progression to overt MAS. Ferritin/ESR ratio may be superior to ferritin alone in discriminating overt MAS from new-onset sJIA.
Anterior Chest Wall Pain in Recent Inflammatory Back Pain Suggestive of Spondyloarthritis. Data from the DESIR Cohort
Authors: Wendling Daniel , Prati Clément , Demattei Christophe , Loeuille Damien , Richette Pascal , Dougados Maxime 
Published: May 2013

Objective.To determine the prevalence of anterior chest wall (ACW) pain in patients with recent inflammatory back pain (IBP) suggestive of spondyloarthritis (SpA), and to investigate the influence of ACW pain on the overall features of these patients.Methods.The DESIR cohort is a prospective, multicenter French cohort of patients with early IBP suggestive of SpA, including 708 patients (mean age 33.8 yrs, 53.8% females, 57.3% HLA-B27-positive). ACW pain was defined by at least 1 episode of chest wall pain attributed to SpA by the rheumatologist, after ruling out other causes of chest pain. Data on the baseline demographic characteristics, functional status and quality of life, imaging features, bone mineral density, and blood tests were compared in patients with and those without ACW pain. Factors associated with ACW pain were identified by univariate and multivariate analysis (logistic regression).Results.The prevalence of ACW pain in the DESIR cohort (n = 316/708 patients) was 44.6% (95% CI 40.9–48.3). ACW pain occurred after the first symptoms of IBP in 62%. Localization was diffuse in 41% of the positive cases. A stepwise multivariate analysis found an association between ACW pain and the enthesitis score, involvement of thoracic spine, diagnosis of ankylosing spondylitis (AS), and radiographic abnormalities of sacroiliac joints.Conclusion.In recent IBP suggestive of SpA, presence of ACW pain is associated with enthesitis, thoracic spine involvement, radiographic sacroiliitis, diagnosis of AS, and with a more severe disease. ACW pain could be interpreted as a diagnostic feature for AS.
Cholesteryl Ester Transfer Protein in Patients with Rheumatoid Arthritis
Authors: Ferraz-Amaro Iván , González-Gay Miguel A. , García-Dopico José A. , Díaz-González Federico 
Published: May 2013

Objective.To investigate how cholesteryl ester transfer protein (CETP), one of the enzymes involved in the reverse cholesterol transfer, is expressed in patients with rheumatoid arthritis (RA) and its potential relationship with both dyslipidemia and the risk of cardiovascular mortality observed in these patients.Methods.Plasma CETP concentrations and CETP activity were measured in 101 patients with RA and 115 sex- and age-matched controls. A multivariable analysis adjusted for standard cardiovascular risk factors, including high-density lipoprotein cholesterol, was performed to evaluate the influence of CETP on dyslipidemia and cardiovascular mortality risk, as assessed by the Systematic Coronary Risk Evaluation (SCORE) risk function.Results.Patients with RA showed lower CETP activity [beta coefficient = −10.82 (95% CI −19.56 to 2.07) pmol/3 h; p = 0.02] and an inferior CETP mass [β = −0.85 (95% CI −1.64 to 0.05)μg/ml; p = 0.03] versus controls. Divided into those taking and those not taking glucocorticoids, patients taking glucocorticoids revealed lower CETP activity and mass [β = −8.98 (95% CI −14.55 to 3.41) pmol/3 h; p = 0.00, for CETP activity; and β = −0.77 (95% CI −1.46 to 0.08)μg/ml; p = 0.03, for CETP mass]. Patients with RA not taking glucocorticoids showed no differences versus controls in either CETP activity or mass. Both current prednisone intake [β = −16.14 (95% CI −24.87 to 7.41) pmol/3 h; p = 0.00] and average daily prednisone intake during the last 3 months [β = −0.36 (95% CI −0.54 to 0.18)μg/ml; p = 0.01] were strongly and inversely correlated with CETP activity and mass, respectively. CETP activity showed an inverse trend compared to SCORE risk, demonstrating that lower levels were effective predictors of total mortality when a higher SCORE risk was found [β = −4.7 (95% CI −9.3 to 0.02) pmol/3 h; p = 0.04] in patients with RA.Conclusion.CETP is downregulated in patients with RA who are taking glucocorticoids. Low CETP activity is associated with an increased level of cardiovascular risk in patients with RA.
Human IL-2 Mutein with Higher Antitumor Efficacy Than Wild Type IL-2
Authors: Carmenate Tania , Pacios Anabel , Enamorado Michel , Moreno Ernesto , Garcia-Martínez Karina , Fuente Dasha , León Kalet 
Published: May 2013

Abstract
IL-2 has been used for the treatment of melanoma and renal cell carcinoma, but this therapy has limited efficacy and severe toxicity. Currently, it is assumed that part of the limited efficacy is due to the IL-2–driven preferential expansion of regulatory T cells, which dampen the antitumor immunity. In this study, we characterize a human IL-2 mutant with higher antitumor efficacy and lower toxicity than wild type human IL-2 (wtIL-2). The mutant differs from wtIL-2 by four mutations at the interface with the α subunit of IL-2R. The IL-2 mutant induces in vitro proliferation of CD8+CD44hi and NK1.1 cells as efficiently as does wtIL-2, but it shows a reduced capacity to induce proliferation of CD4+Foxp3+ regulatory T cells. The IL-2 mutant shows a higher antimetastatic effect than does wtIL-2 in several transplantable tumor models: the experimental metastasis model of MB16F0 melanoma and the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222. Relevantly, the IL-2 mutant also exhibits lower lung and liver toxicity than does wtIL-2 when used at high doses in mice. In silico simulations, using a calibrated mathematical model, predict that the properties of IL-2 mutein are a consequence of the reduction, of at least two orders of magnitude, in its affinity for the α subunit of IL-2R (CD25). The human IL-2 mutant described in the present work could be a good candidate for improving cancer therapy based on IL-2.
Assembly of the TLR2/6 Transmembrane Domains Is Essential for Activation and Is a Target for Prevention of Sepsis
Authors: Fink Avner , Reuven Eliran M. , Arnusch Christopher J. , Shmuel-Galia Liraz , Antonovsky Niv , Shai Yechiel 
Published: May 2013

Abstract
TLR2, together with TLR1 and TLR6, is essential for detecting lipopeptides and bacterial cell wall components such as lipoteichoic acid from Gram-positive bacteria. In this study, we report that transmembrane domain (TMD)–derived peptides from TLR2 and TLR6 specifically inhibit TLR2 activation. Secretion of the cytokines TNF-α and IL-6 by cultured macrophages (RAW264.7 cell line) was inhibited by these peptides in response to TLR2 activation by lipoteichoic acid (TLR2/6 activator) or palmitoyl (3)-Cys-Ser-Lys(4)-OH (TLR2/1 activator) but not by LPS (TLR4 activator). Extensive biophysical and biochemical assays, combined with GALLEX experiments, show that these peptides heterodimerize with their complementary TMDs on their reciprocal protein. These results suggest that TLR2/6/1 TMD assembly is essential for activating this complex. Importantly, when administered to mice inflicted by TLR2, but not TLR4-driven lethal inflammation, a selected peptide rescued 60% of these septic mice, showing potent in vivo inhibition of TNF-α and IL-6 secretion. Furthermore, this peptide also showed high protection in a whole bacteria model. Owing to the importance of TLR2 regulation under a variety of pathological conditions, compounds that can fine-tune this activity are of great importance.
Dipeptidyl Peptidase IV Is a Human and Murine Neutrophil Chemorepellent
Authors: Herlihy Sarah E. , Pilling Darrell , Maharjan Anu S. , Gomer Richard H. 
Published: May 2013

Abstract
In Dictyostelium discoideum, AprA is a secreted protein that inhibits proliferation and causes chemorepulsion of Dictyostelium cells, yet AprA has little sequence similarity to any human proteins. We found that a predicted structure of AprA has similarity to human dipeptidyl peptidase IV (DPPIV). DPPIV is a serine protease present in extracellular fluids that cleaves peptides with a proline or alanine in the second position. In Insall chambers, DPPIV gradients below, similar to, and above the human serum DPPIV concentration cause movement of human neutrophils away from the higher concentration of DPPIV. A 1% DPPIV concentration difference between the front and back of the cell is sufficient to cause chemorepulsion. Neutrophil speed and viability are unaffected by DPPIV. DPPIV inhibitors block DPPIV-mediated chemorepulsion. In a murine model of acute respiratory distress syndrome, aspirated bleomycin induces a significant increase in the number of neutrophils in the lungs after 3 d. Oropharyngeal aspiration of DPPIV inhibits the bleomycin-induced accumulation of mouse neutrophils. These results indicate that DPPIV functions as a chemorepellent of human and mouse neutrophils, and they suggest new mechanisms to inhibit neutrophil accumulation in acute respiratory distress syndrome.
Canonical and Noncanonical Wnt Proteins Program Dendritic Cell Responses for Tolerance
Authors: Oderup Cecilia , LaJevic Melissa , Butcher Eugene C. 
Published: May 2013

Abstract
Ag-presenting dendritic cells (DCs) interpret environmental signals to orchestrate local and systemic immune responses. They govern the balance between tolerance and inflammation at epithelial surfaces, where the immune system must provide robust pathogen responses while maintaining tolerance to commensal flora and food Ags. The Wnt family of secreted proteins, which control epithelial and hematopoietic development and homeostasis, is emerging as an important regulator of inflammation. In this study, we show that canonical and noncanonical Wnts directly stimulate murine DC production of anti-inflammatory cytokines. Wnt3A triggers canonical β-catenin signaling and preferentially induces DC TGF-β and VEGF production, whereas Wnt5A induces IL-10 through alternative pathways. The Wnts also alter DC responses to microbe- or pathogen-associated molecular patterns, inhibiting proinflammatory cytokine induction in response to TLR ligands and promoting DC generation of Foxp3+ regulatory T cells. Moreover, although both Wnts suppress proinflammatory responses to bacterial endotoxin and to TLR1/2, TLR7, and TLR9 ligands, Wnt5A, but not Wnt3A, inhibits IL-6 production in response to the viral mimic, polyinosinic:polycytidylic acid. Thus, Wnt family members directly and differentially regulate DC functions, an ability that may contribute to the balance between tolerance and inflammation at epithelial sites of exposure to microbes and environmental Ags.
CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway
Authors: Chen Zhubo , Han Yanmei , Gu Yan , Liu Yanfang , Jiang Zhengping , Zhang Minghui , Cao Xuetao 
Published: May 2013

AbstractRegulatory T cells can restrict the uncontrolled immune response and inflammation, avoiding pathologic immune injury to the host and thus playing important roles in the maintenance of immune homeostasis. Until recently, many subsets of CD4 and CD8 regulatory T cells have been reported. In this study, we identified CD11chighCD8+ T cells as a new subset of CD8+ regulatory T cells. During Listeria monocytogenes and Staphylococcus aureus infection, two subsets of CD8 T cells were classified according to the expression level of CD11c, including CD11clowCD8+ and CD11chighCD8+ T cells. CD11clowCD8+ T cells, existing during the whole period of infection, act as conventional activated T cells to kill target cells in a perforin-dependent manner. Interestingly, CD11chighCD8+ T cells appeared only at a late stage of infection, expressed relatively high CD122 and low CD69, did not secrete IFN-γ, IL-10, TGF-β, and exhibited much more potent cytotoxicity against target cells via Fas ligand–Fas pathway in an Ag-independent manner. Ligation of CD11c was important in the cytotoxicity of CD11chighCD8+ T cells. Furthermore, CD11chighCD8+ T cells could directly kill the activated CD4 T cells both in vitro and in vivo, whereas CD11clowCD8+ T cells could not. Thus, we identified an infection-induced new subset of CD11chighCD8+ regulatory T cells, which might contribute to protect host from pathological immune injure. Our results indicate that CD11c+CD8+ T cells are constitute a heterogeneous population that can be divided further into regulatory CD11chighCD8+ T cell subset and effector CD11clowCD8+ T cell subset, thus adding insight to the role of CD8 T cells in immune response and regulation.
Accelerated Turnover of MHC Class II Molecules in Nonobese Diabetic Mice Is Developmentally and Environmentally Regulated In Vivo and Dispensable for Autoimmunity
Authors: De Riva Alessandra , Varley Mark C. , Bluck Leslie J. , Cooke Anne , Deery Michael J. , Busch Robert 
Published: May 2013

AbstractThe H2-Ag7 (Ag7) MHC class II (MHCII) allele is required for type 1 diabetes (T1D) in NOD mice. Ag7 not only has a unique peptide-binding profile, it was reported to exhibit biochemical defects, including accelerated protein turnover. Such defects were proposed to impair Ag presentation and, thus, self-tolerance. Here, we report measurements of MHCII protein synthesis and turnover in vivo. NOD mice and BALB/c controls were labeled continuously with heavy water, and splenic B cells and dendritic cells were isolated. MHCII molecules were immunoprecipitated and digested with trypsin. Digests were analyzed by liquid chromatography/mass spectrometry to quantify the fraction of newly synthesized MHCII molecules and, thus, turnover. MHCII turnover was faster in dendritic cells than in B cells, varying slightly between mouse strains. Some Ag7 molecules exhibited accelerated turnover in B cells from young, but not older, prediabetic female NOD mice. This acceleration was not detected in a second NOD colony with a high incidence of T1D. Turnover rates of Ag7 and H2-Ad were indistinguishable in (NOD × BALB/c) F1 mice. In conclusion, accelerated MHCII turnover may occur in NOD mice, but it reflects environmental and developmental regulation, rather than a structural deficit of the Ag7 allele. Moreover, this phenotype wanes before the onset of overt T1D and is dispensable for the development of autoimmune diabetes. Our observations highlight the importance of in vivo studies in understanding the role of protein turnover in genotype/phenotype relationships and offer a novel approach for addressing this fundamental research challenge.
Neural Precursor Cells Cultured at Physiologically Relevant Oxygen Tensions Have a Survival Advantage Following Transplantation
Authors: Stacpoole Sybil R.L. , Webber Daniel J. , Bilican Bilada , Compston Alastair , Chandran Siddharthan , Franklin Robin J.M. 
Published: May 2013

Abstract
Traditionally, in vitro stem cell systems have used oxygen tensions that are far removed from the in vivo situation. This is particularly true for the central nervous system, where oxygen (O2) levels range from 8% at the pia to 0.5% in the midbrain, whereas cells are usually cultured in a 20% O2 environment. Cell transplantation strategies therefore typically introduce a stress challenge at the time of transplantation as the cells are switched from 20% to 3% O2 (the average in adult organs). We have modeled the oxygen stress that occurs during transplantation, demonstrating that in vitro transfer of neonatal rat cortical neural precursor cells (NPCs) from a 20% to a 3% O2 environment results in significant cell death, whereas maintenance at 3% O2 is protective. This survival benefit translates to the in vivo environment, where culture of NPCs at 3% rather than 20% O2 approximately doubles survival in the immediate post-transplantation phase. Furthermore, NPC fate is affected by culture at low, physiological O2 tensions (3%), with particularly marked effects on the oligodendrocyte lineage, both in vitro and in vivo. We propose that careful consideration of physiological oxygen environments, and particularly changes in oxygen tension, has relevance for the practical approaches to cellular therapies.
Perspectives on Stem Cell-Based Elastic Matrix Regenerative Therapies for Abdominal Aortic Aneurysms
Authors: Bashur Chris A. , Rao Raj R. , Ramamurthi Anand 
Published: May 2013

Summary
Abdominal aortic aneurysms (AAAs) are potentially fatal conditions that are characterized by decreased flexibility of the aortic wall due to proteolytic loss of the structural matrix. This leads to their gradual weakening and ultimate rupture. Drug-based inhibition of proteolytic enzymes may provide a nonsurgical treatment alternative for growing AAAs, although it might at best be sufficient to slow their growth. Regenerative repair of disrupted elastic matrix is required if regression of AAAs to a healthy state is to be achieved. Terminally differentiated adult and diseased vascular cells are poorly capable of affecting such regenerative repair. In this context, stem cells and their smooth muscle cell-like derivatives may represent alternate cell sources for regenerative AAA cell therapies. This article examines the pros and cons of using different autologous stem cell sources for AAA therapy, the requirements they must fulfill to provide therapeutic benefit, and the current progress toward characterizing the cells' ability to synthesize elastin, assemble elastic matrix structures, and influence the regenerative potential of diseased vascular cell types. The article also provides a detailed perspective on the limitations, uncertainties, and challenges that will need to be overcome or circumvented to translate current strategies for stem cell use into clinically viable AAA therapies. These therapies will provide a much needed nonsurgical treatment option for the rapidly growing, high-risk, and vulnerable elderly demographic.
A New Phase Boundary in (Bi1/2Na1/2)TiO3−BaTiO3 Revealed via a Novel Method of Electron Diffraction Analysis
Authors: Ma Cheng , Guo Hanzheng , Tan Xiaoli 
Published: May 2013

AbstractA new phase boundary is revealed in (1–x)(Bi1/2Na1/2)TiO3−xBaTiO3, the most extensively studied lead‐free piezoelectric solid solution. This discovery results from a novel method of electron diffraction analysis, which allows the precise determination of oxygen octahedra tilting in multi‐domain perovskite ferroelectrics. The study using this method supports the recently proposed Cc symmetry for pure (Bi1/2Na1/2)TiO3, and, more importantly, indicates the crystal structure evolves into the R3c symmetry with the addition of BaTiO3, forming a Cc/R3c phase boundary at x = 3–4%. In the poling field Epol versus composition x phase diagram for polycrystalline ceramics, this phase boundary exists with Epol below 5.5 kV mm−1; the Cc phase is transformed to the R3c phase during poling at higher fields. The results reported here provide the microstructural origin for the previously unexplained strain behavior and clarify the low‐BaTiO3‐content phase relationship in this popular lead‐free piezoelectric system.
Intraphase Microstructure–Understanding the Impact on Organic Solar Cell Performance
Authors: Scholes Fiona H. , Ehlig Tino , James Michael , Lee Kwan H. , Duffy Noel , Scully Andrew D. , Singh T. Birenda , Winzenberg Kevin N. , Kemppinen Pete , Watkins Scott E. 
Published: May 2013

AbstractA comprehensive study of the effect of intraphase microstructure on organic photovoltaic (OPV) device performance is undertaken. Utilizing a bilayer device architecture, a small molecule donor (TIPS‐DBC) is deposited by both spin‐coating and by thermal evaporation in vacuum. The devices are then completed by thermal evaporation of C60, an exciton blocking layer and the cathode. This bilayer approach enables a direct comparison of device performance for donor layers in which the same material exhibits subtle differences in microstructure. The electrical performance is shown to differ considerably for the two devices. The bulk and interfacial properties of the donor layers are compared by examination with photoelectron spectroscopy in air (PESA), optical absorption spectroscopy, charge extraction of photo‐generated charge carriers by linearly increasing voltage (photo‐CELIV), time‐resolved photoluminescence measurements, X‐ray reflectometry (XR), and analysis of dark current behavior. The observed differences in device performance are shown to be influenced by changes to energy levels and charge transport properties resulting from differences in the microstructure of the donor layers. Importantly, this work demonstrates that in addition to the donor/acceptor microstructure, the intraphase microstructure can influence critical parameters and can therefore have a significant impact on OPV performance.
Synthesis of 2‐Substituted Benzothiazoles by Visible Light‐Driven Photoredox Catalysis
Authors: Yu Chunghyeon , Lee Kyungyub , You Youngmin , Cho Eun Jin 
Published: May 2013

AbstractAn efficient method for synthesis of the widely applicable 2‐substituted benzothiazoles has been developed. The process requires only 0.1 mol% [Ru(bpy)3Cl2], O2, and visible light irradiation with substrates: 2‐aminothiophenol and a variety of aldehydes. We established an oxidative quenching of the photoredox catalyst as being the key process in this photoelectrocatalytic cycle.