bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the Ability of Geophysical Methods to Image Medieval Turf Buildings in Iceland
Authors: Wunderlich Tina , Wilken Dennis , Andersen Jasmin , Rabbel Wolfgang , Zori Davide , Kalmring Sven , Byock Jesse 
Published: March 2015

AbstractStructures in Iceland were traditionally built of turf, earth and, to a lesser extent, stone. As turf was the primary construction material, the contrast in geophysical parameters between building ruins and surrounding soil is expected to be low. To investigate the extent to which the remains of turf buildings can be detected by geophysical measurements, we applied several geophysical techniques to a known turf ruin in southwestern Iceland. The methods used were magnetics, ground‐penetrating radar (GPR), electromagnetic induction (EMI), electrical resistivity tomography (ERT) and seismic Rayleigh‐wave resonance mapping (RRM). Magnetics identified an accumulation of stones inside and beside the ruin. The in‐phase component of the EMI measurements, which can be related to magnetic susceptibility, showed the same pattern. A very precise image of the stones lining the inside of the former turf walls was generated by GPR. In contrast, EMI conductivity and ERT imaged the actual turf in the walls. Turf walls have lower electrical conductivity compared with the surrounding soil, probably as a result of different porosities. The mapping of Rayleigh wave resonance clearly revealed the outline of the ruin, as indicated by weaker amplitudes compared with the surrounding soil. Overall the results indicate that geophysical methods can be used for subsurface mapping of Icelandic turf structures and that the combined application of the methods maximizes this potential. Copyright © 2015 John Wiley & Sons, Ltd.
Autoantigen BiP‐Derived HLA–DR4 Epitopes Differentially Recognized by Effector and Regulatory T Cells in Rheumatoid Arthritis
Authors: Shoda Hirofumi , Fujio Keishi , Sakurai Keiichi , Ishigaki Kazuyoshi , Nagafuchi Yasuo , Shibuya Mihoko , Sumitomo Shuji , Okamura Tomohisa , Yamamoto Kazuhiko 
Published: March 2015

ObjectiveThe balance between effector and regulatory CD4+ T cells plays a key role in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to examine whether the RA autoantigen BiP has epitopes for both effector and regulatory immunities.MethodsThe proliferation and cytokine secretion of peripheral blood mononuclear cells (PBMCs) from HLA–DR4–positive RA patients in response to BiP‐derived peptides were examined by 3H‐thymidine uptake and enzyme‐linked immunosorbent assay. As a mouse therapeutic model, a BiP‐derived peptide was administered orally to mice with collagen‐induced arthritis (CIA).ResultsAmong the peptides examined, BiP336–355 induced the strongest proliferation of PBMCs from RA patients, but not from healthy donors. The proliferation of PBMCs in response to BiP336–355 showed a correlation with clinical RA activity and serum anti‐BiP/citrullinated BiP antibodies. In contrast, BiP456–475 induced interleukin‐10 (IL‐10) secretion from CD25‐positive PBMCs obtained from RA patients and healthy donors without inducing cell proliferation, and it actively suppressed the BiP336–355–induced proliferation and proinflammatory cytokine secretion by PBMCs. Oral administration of BiP456–475 to mice with CIA reduced the severity of arthritis and T cell proliferation and increased the secretion of IL‐10 from T cells as well as the number of CD4+CD25+FoxP3+ regulatory T cells.ConclusionEffector and regulatory T cells recognized different BiP epitopes. The deviated balance toward BiP‐specific effector T cells in RA may be associated with disease activity; therefore, BiP‐specific effector or regulatory T cells could be a target of new RA therapies.
Nested Case–Control Study of Selected Systemic Autoimmune Diseases in World Trade Center Rescue/Recovery Workers
Authors: Webber M. P. , Moir W. , Zeig‐Owens R. , Glaser M. S. , Jaber N. , Hall C. , Berman J. , Qayyum B. , Loupasakis K. , Kelly K. , Prezant D. J. 
Published: March 2015

ObjectiveTo test the a priori hypothesis that acute and chronic work exposures to the World Trade Center (WTC) site on or after September 11, 2001 were associated with risk of new‐onset systemic autoimmune diseases.MethodsA nested case–control study was performed in WTC rescue/recovery workers who had received a rheumatologist‐confirmed systemic autoimmune disease diagnosis between September 12, 2001 and September 11, 2013 (n = 59), each of whom was individually matched to 4 randomly selected controls (n = 236) on the basis of year of hire (±1 year), sex, race, and work assignment (firefighter or emergency medical service). Acute exposure was defined according to the earliest time of arrival (morning of 9/11 versus later) at the WTC site, and chronic exposure was defined as duration (number of months) of WTC site–related work. Rheumatologists were blinded with regard to each subject's exposure status. The conditional odds ratios (CORs) with 95% confidence intervals (95% CIs) for incident autoimmune disease were derived from exact conditional logistic regression models.ResultsRheumatoid arthritis was the most common autoimmune diagnosis (37% of subjects), followed by spondyloarthritis (22%), inflammatory myositis (14%), systemic lupus erythematosus (12%), systemic sclerosis (5%), Sjögren's syndrome (5%), antiphospholipid syndrome (3%), and granulomatosis with polyangiitis (Wegener's) (2%). The COR for incident autoimmune disease increased by 13% (COR 1.13, 95% CI 1.02–1.26) for each additional month worked at the WTC site. These odds were independent of the association between high acute exposure (working during the morning of 9/11) and disease outcome, which conveyed an elevated, but not statistically significant, risk (COR 1.85, 95% CI 0.86–3.89).ConclusionProlonged work at the WTC site, independent of acute exposure, was an important predictor of post‐9/11 systemic autoimmune diseases. The WTC Health Program should expand surveillance efforts for those with extended exposures, as early detection can facilitate early treatment, which has been shown to minimize organ damage and improve quality of life.
Interleukin‐1 Acts via the JNK‐2 Signaling Pathway to Induce Aggrecan Degradation by Human Chondrocytes
Authors: Ismail Heba M. , Yamamoto Kazuhiro , Vincent Tonia L. , Nagase Hideaki , Troeberg Linda , Saklatvala Jeremy 
Published: March 2015

ObjectiveAggrecan enables articular cartilage to bear load and resist compression. Aggrecan loss occurs early in osteoarthritis and rheumatoid arthritis and can be induced by inflammatory cytokines such as interleukin‐1 (IL‐1). IL‐1 induces cleavage of specific aggrecans characteristic of the ADAMTS proteinases. The aim of this study was to identify the intracellular signaling pathways by which IL‐1 causes aggrecan degradation by human chondrocytes and to investigate how aggrecanase activity is controlled by chondrocytes.MethodsWe developed a cell‐based assay combining small interfering RNA (siRNA)–induced knockdown with aggrecan degradation assays. Human articular chondrocytes were overlaid with bovine aggrecan after transfection with siRNAs against molecules of the IL‐1 signaling pathway. After IL‐1 stimulation, released aggrecan fragments were detected with AGEG and ARGS neoepitope antibodies. Aggrecanase activity and tissue inhibitor of metalloproteinases 3 levels were measured by enzyme‐linked immunosorbent assay. Low‐density lipoprotein receptor–related protein 1 (LRP‐1) shedding was analyzed by Western blotting.ResultsADAMTS‐5 is a major aggrecanase in human chondrocytes, regulating aggrecan degradation in response to IL‐1. The tumor necrosis factor receptor–associated 6 (TRAF‐6)/transforming growth factor β–activated kinase 1 (TAK‐1)/MKK‐4 signaling axis is essential for IL‐1–induced aggrecan degradation, while NF‐κB is not. Of the 3 MAPKs (ERK, p38, and JNK), only JNK‐2 showed a significant role in aggrecan degradation. Chondrocytes constitutively secreted aggrecanase, which was continuously endocytosed by LRP‐1, keeping the extracellular level of aggrecanase low. IL‐1 induced aggrecanase activity in the medium in a JNK‐2–dependent manner, possibly by reducing aggrecanase endocytosis, because IL‐1 caused JNK‐2–dependent shedding of LRP‐1.ConclusionThe signaling axis TRAF‐6/TAK‐1/MKK‐4/JNK‐2 mediates IL‐1–induced aggrecanolysis. The level of aggrecanase is controlled by its endocytosis, which may be reduced upon IL‐1 stimulation because of LRP‐1 shedding.
Suppression of Autoimmunity and Renal Disease in Pristane‐Induced Lupus by Myeloperoxidase
Authors: Odobasic Dragana , Muljadi Ruth C. M. , O'Sullivan Kim M. , Kettle Anthony J. , Dickerhof Nina , Summers Shaun A. , Kitching A. Richard , Holdsworth Stephen R. 
Published: March 2015

ObjectiveMyeloperoxidase (MPO) locally contributes to organ damage in various chronic inflammatory conditions by generating reactive intermediates. The contribution of MPO in the development of experimental lupus is unknown. The aim of this study was to define the role of MPO in murine lupus nephritis (LN).MethodsLN was induced in C57BL/6 wild‐type (WT) and MPO knockout (MPO–/–) mice by intraperitoneal injection of pristane. Autoimmunity and glomerulonephritis were assessed 20 and 40 weeks after pristane administration. Cell apoptosis, leukocyte accumulation, and cytokine levels in the peritoneal cavity of WT and MPO–/– mice were assessed 3 or 6 days after pristane injection.ResultsMPO–/– mice developed more severe nephritis than did WT mice 20 and 40 weeks after pristane injection, despite having reduced glomerular deposition of antibody and complement and diminished levels of markers of oxidative stress (oxidized DNA and glutathione sulfonamide). Enhancement of renal disease in MPO‐deficient mice correlated with increased accumulation of CD4+ T cells and macrophages in glomeruli, which, in turn, was associated with augmented generation of CD4+ T cell responses and increased activation and migration of dendritic cells in secondary lymphoid organs. In addition, the enhanced renal injury in MPO–/– mice was associated with increased glomerular accumulation of neutrophils and deposition of neutrophil extracellular traps. MPO deficiency also increased early cell apoptosis, leukocyte accumulation, and proinflammatory cytokine expression in the peritoneum.ConclusionMPO attenuates pristane‐induced LN by inhibiting early inflammatory responses in the peritoneum and limiting the generation of CD4+ T cell autoimmunity in secondary lymphoid organs.
Hip Osteoarthritis and the Risk of All‐Cause and Disease‐Specific Mortality in Older Women: A Population‐Based Cohort Study
Authors: Barbour Kamil E. , Lui Li‐Yung , Nevitt Michael C. , Murphy Louise B. , Helmick Charles G. , Theis Kristina A. , Hochberg Marc C. , Lane Nancy E. , Hootman Jennifer M. , Cauley Jane A. ,   for the Study of Osteoporotic Fractures Research Group
Published: March 2015

ObjectiveTo determine the risk of all‐cause and disease‐specific mortality among older women with hip osteoarthritis (OA) and to identify mediators in the causal pathway.MethodsData were from the Study of Osteoporotic Fractures, a US population‐based cohort study of 9,704 white women age ≥65 years. The analytic sample included women with hip radiographs at baseline (n = 7,889) and year 8 (n = 5,749). Mortality was confirmed through October 2013 by death certificates and hospital discharge summaries. Radiographic hip OA (RHOA) was defined as a Croft grade of ≥2 in at least 1 hip (definite joint space narrowing or osteophytes plus 1 other radiographic feature).ResultsThe mean ± SD followup time was 16.1 ± 6.2 years. The baseline and year 8 prevalence of RHOA were 8.0% and 11.0%, respectively. The cumulative incidence (proportion of deaths during the study period) was 67.7% for all‐cause mortality, 26.3% for cardiovascular disease (CVD) mortality, 11.7% for cancer mortality, 1.9% for gastrointestinal disease mortality, and 27.8% for all other mortality causes. RHOA was associated with an increased risk of all‐cause mortality (hazard ratio 1.14 [95% confidence interval 1.05–1.24]) and CVD mortality (hazard ratio 1.24 [95% confidence interval 1.09–1.41]) adjusted for age, body mass index, education, smoking, health status, diabetes, and stroke. These associations were partially explained by the mediating variable of physical function.ConclusionRHOA was associated with an increased risk of all‐cause and CVD mortality among older white women followed up for 16 years. Dissemination of evidence‐based physical activity and self‐management interventions for hip OA in community and clinical settings can improve physical function and might also contribute to lower mortality.
Role of EFNB1 and EFNB2 in Mouse Collagen‐Induced Arthritis and Human Rheumatoid Arthritis
Authors: Hu Yan , Wang Xuehai , Wu Yongqiang , Jin Wei , Cheng Baoli , Fang Xiangming , Martel‐Pelletier Johanne , Kapoor Mohit , Peng Junzheng , Qi Shijie , Shi Guixiu , Wu Jiangping , Luo Hongyu 
Published: March 2015

ObjectiveEFNB1 and EFNB2 are ligands for Eph receptor tyrosine kinases. This study was undertaken to investigate how the expression of Efnb1 and Efnb2 on murine T cells influences the pathogenesis of collagen‐induced arthritis (CIA) and to assess correlations between the T cell expression of these 2 molecules and measures of disease activity in patients with rheumatoid arthritis (RA).MethodsCIA was studied in mice with T cell–specific deletion (double gene knockout [dKO]) of both Efnb1 and Efnb2. Expression of EFNB1 and EFNB2 messenger RNA (mRNA) in peripheral blood T cells from patients with RA was determined by quantitative reverse transcription– polymerase chain reaction.ResultsIn dKO mice, clinical scores of arthritis were reduced compared to those in wild‐type (WT) control mice. Serum collagen‐specific antibody titers in dKO mice were lower than those in WT mice. In analyses based on equal cell numbers, dKO mouse T cells, as compared to WT mouse T cells, provided vastly inferior help to B cells in the production of collagen‐specific antibodies in vitro. T cells from dKO mice were compromised in their ability to migrate to the arthritic paws in vivo and in their ability to undergo chemotaxis toward CXCL12 in vitro. Deletion mutation of Efnb1 and Efnb2 intracellular tails revealed critical regions in controlling T cell chemotaxis. T cells from RA patients expressed higher EFNB1 mRNA levels, which correlated with RA symptoms and laboratory findings.ConclusionEfnb1 and Efnb2 in T cells are essential for pathogenic antibody production and for T cell migration to the inflamed paws in mice with CIA. These findings suggest that the expression of EFNB1 in T cells might be a useful parameter for monitoring RA disease activity and treatment responses.
CCR2 Expression in Neutrophils Plays a Critical Role in Their Migration Into the Joints in Rheumatoid Arthritis
Authors: Talbot Jhimmy , Bianchini Francine J. , Nascimento Danilele C. , Oliveira Rene D. R. , Souto Fabricio O. , Pinto Larissa G. , Peres Raphael S. , Silva Jaqueline R. , Almeida Sergio C. L. , Louzada‐Junior Paulo , Cunha Thiago M. , Cunha Fernando Q. , Alves‐Filho Jose C. 
Published: March 2015

ObjectiveInfiltration of neutrophils into the joints plays an important role in bone erosion and articular destruction in rheumatoid arthritis (RA). Neutrophil trafficking during inflammation is a process that involves activation of chemotactic receptors. Recent findings suggest that changes in chemotactic receptor patterns could occur in neutrophils under certain inflammatory conditions. The aim of this study was to evaluate the gain of responsiveness of neutrophils to CCL2 in RA patients and to assess the role of CCL2 in driving neutrophil infiltration into the joints.MethodsNeutrophils were purified from the peripheral blood of patients with RA or from mice with antigen‐induced arthritis (AIA). Expression of CCR2 was evaluated using polymerase chain reaction, flow cytometry, and immunofluorescence analyses. In vitro chemotaxis to CCL2 was assayed to evaluate the functional significance of de novo CCR2 expression. The murine AIA model was used to evaluate the in vivo role of CCR2 in neutrophil infiltration into the joints.ResultsHigh CCR2 expression and responsiveness to CCL2 were observed in neutrophils from the blood of patients with early RA and in neutrophils from the blood and bone marrow of mice with AIA. Genetic deficiency or pharmacologic inhibition of CCR2 protected against the infiltration of neutrophils into the joints. This protection was not associated with an impairment of the neutrophil chemotactic ability or CXC chemokine production in the joints. Moreover, adoptive transfer of wild‐type mouse neutrophils to CCR2‐deficient mice restored neutrophil infiltration and the articular mechanical hyperalgesia associated with joint inflammation.ConclusionThese findings suggest that CCR2 is directly involved in the detrimental infiltration of neutrophils into the joints in patients with RA, showing a new inflammatory role of CCR2 during RA flares or active disease.
The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl‐DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis
Authors: Keil Andreas , Frese‐Schaper Manuela , Steiner Selina K. , Körner Meike , Schmid Ralph A. , Frese Steffen 
Published: March 2015

ObjectiveThe treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. While irinotecan is known to stabilize the complex of topo I and DNA, the enzyme tyrosyl‐DNA phosphodiesterase 1 (TDP‐1) functions in an opposing manner by releasing topo I from DNA. Therefore, we undertook this study to test whether the TDP‐1 inhibitor furamidine has an additional effect on lupus nephritis when used in combination with irinotecan.MethodsNZB/NZW mice were treated with low‐dose irinotecan and furamidine either alone or in combination beginning at age 26 weeks. DNA relaxation was visualized using gel electrophoresis. Binding of anti–double‐stranded DNA (anti‐dsDNA) antibodies to DNA modified by topo I, TDP‐1, and the topo I inhibitor camptothecin was determined by enzyme‐linked immunosorbent assay.ResultsCompared to treatment with either agent alone, simultaneous treatment with low‐dose irinotecan and furamidine significantly improved survival of NZB/NZW mice. Similar to what has been previously shown for irinotecan alone, the combination treatment did not change the levels of anti‐dsDNA antibodies. In vitro, recombinant TDP‐1 increased topo I–mediated DNA relaxation, resulting in enhanced binding of anti‐dsDNA antibodies. In combination with topo I and camptothecin, TDP‐1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti‐dsDNA binding.ConclusionAffecting DNA relaxation by the enzymes topo I and TDP‐1 and their inhibitors may be a promising approach for the development of new targeted therapies for systemic lupus erythematosus.
Apremilast in Patients With Active Rheumatoid Arthritis: A Phase II, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study
Authors: Genovese Mark C. , Jarosova Katerina , Cieślak Dorota , Alper Jeffrey , Kivitz Alan , Hough Douglas R. , Maes Peter , Pineda Lilia , Chen Mindy , Zaidi Farrukh 
Published: March 2015

ObjectiveTo study the efficacy/safety of apremilast, an oral phosphodiesterase 4 inhibitor, compared with placebo in patients with active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX).MethodsPatients were randomized 1:1:1 to receive placebo, apremilast 20 mg twice a day, or apremilast 30 mg twice a day. Patients whose swollen and tender joint counts had not improved by ≥20% were considered nonresponders at week 16 and were required to enter the protocol‐defined early escape. At week 24, patients were transitioned in a blinded manner to receive apremilast 20 mg twice a day if they were initially randomized to receive placebo. Patients who were not initially randomized to receive placebo continued to receive their target apremilast dose. Patients were required to take a stable dose of MTX (7.5–25 mg/week) throughout the study. Magnetic resonance imaging (MRI) was performed in a subset of patients.ResultsA total of 237 patients who were receiving MTX therapy were randomized and received ≥1 dose of study medication. At week 16, similar proportions of patients receiving placebo (35%), apremilast 20 mg twice a day (28%), and apremilast 30 mg twice a day (34%) met the American College of Rheumatology criteria for 20% improvement in disease activity (the primary efficacy end point). In the MRI substudy, mean change from baseline in total joint damage scores according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system was generally similar with either apremilast dose at week 16. At week 52, no trends were noted for clinical end points by treatment group. Both apremilast doses were generally well tolerated.ConclusionApremilast efficacy was not demonstrated in patients who had active RA despite stable MTX therapy.
Aluminum oxide nanoparticles alter cell cycle progression through CCND1 and EGR1 gene expression in human mesenchymal stem cells
Authors: Periasamy Vaiyapuri Subbarayan , Athinarayanan Jegan , Alshatwi Ali A. 
Published: March 2015

AbstractAluminum oxide nanoparticles (Al2O3‐NPs) are important ceramic materials that have been used in a variety of commercial and industrial applications. However, the impact of acute and chronic exposure to Al2O3‐NPs on the environment and on human health has not been well studied. In this investigation, we evaluated the cytotoxic effects of Al2O3‐NPs on human mesenchymal stem cells (hMSCs) by using a cell viability assay and observing cellular morphological changes, analyzing cell cycle progression, and monitoring the expression of cell cycle response genes (PCNA, EGR1, E2F1, CCND1, CCNC, CCNG1, and CYCD3). The Al2O3‐NPs reduced hMSC viability in a dose‐ and time‐dependent manner. Nuclear condensation and fragmentation, chromosomal DNA fragmentation, and cytoplasmic vacuolization were observed in Al2O3‐NP‐exposed cells. The nuclear morphological changes indicated that Al2O3‐NPs alter cell cycle progression and gene expression. The cell cycle distribution revealed that Al2O3‐NPs cause cell cycle arrest in the sub‐G0‐G1 phase, and this is associated with a reduction in the cell population in the G2/M and G0/G1 phases. Moreover, Al2O3‐NPs induced the upregulation of cell cycle response genes, including EGR1, E2F1, and CCND1. Our results suggested that exposure to Al2O3‐NPs could cause acute cytotoxic effects in hMSCs through cell cycle regulatory genes.