bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of Hydroxychloroquine Use With Lipid Profiles in Rheumatoid Arthritis: Pharmacologic Implications
Authors: Kerr Gail , Aujero Mireille , Richards John , Sayles Harlan , Davis Lisa , Cannon Grant , Caplan Liron , Michaud Kaleb , Mikuls Ted 
Published: April 2014

ObjectiveTo evaluate the association of hydroxychloroquine (HCQ) use with lipid profiles in a Veterans Affairs Rheumatoid Arthritis (VARA) cohort.MethodsLipid profiles in HCQ users were compared with HCQ nonusers, adjusting for potential confounders (age, sex, race, disease activity, prednisone, disease‐modifying antirheumatic drugs, diabetes mellitus, and statin use). Applying current National Cholesterol Education Program Adult Treatment Panel III (NCEP‐ATP III) guidelines for reduction of cardiovascular disease (CVD) events risk, the frequency of target lipid profiles with HCQ status was evaluated. Varied periods of HCQ exposure were compared to ascertain pharmacologic associations with lipid values. CVDs were compared between HCQ users and nonusers.ResultsIn an elderly, predominantly male VARA cohort, 1,011 patients had lipid profiles; 787 patients (77.8%) were white. Statin use was recorded in 11.6% of patients, diabetes mellitus in 33.5%, and CVD in 31.2%. HCQ users (n = 150) were older, had longer rheumatoid arthritis (RA) disease duration, and had lower disease activity. Optimum lipid profiles, including total cholesterol:high‐density lipoprotein (HDL) and HDL:low‐density lipoprotein ratios (P ≤ 0.001), were more frequent in HCQ users, with the exception of HDL (P = 0.165), and persisted in multivariate analyses. Similarly, more HCQ users had NCEP‐ATP III target levels. Varied periods of HCQ exposure suggested lipid changes to occur early, but lost within a year of drug discontinuation. HCQ users had less prevalent CVD.ConclusionIn RA patients, HCQ use of at least 3 months' duration was associated with better lipid profiles irrespective of disease activity or statin use. Given the increased CVD risks in RA and the relative low cost and toxicity of HCQ, continued use, regardless of treatment regimen, should be considered.
Cinchona Alkaloids as Organocatalysts in Enantioselective Halofunctionalization of Alkenes and Alkynes
Authors: Zheng Suqing , Schienebeck Casi M. , Zhang Wei , Wang Hao‐Yuan , Tang Weiping 
Published: April 2014

AbstractNaturally occurring cinchona alkaloids include quinine, quinidine, cinchonine, and cinchonidine. Many of their derivatives are also readily available. This Focus Review summarizes recent applications of cinchona alkaloid derivatives, an important class of organocatalysts, in enantioselective halofunctionalization of alkenes and alkynes. Most successful examples in this area are intramolecular halofunctionalizations, where the nucleophile is tethered with the alkene or alkyne substrate. Only a few catalytic enantioselective intermolecular halofunctionalization of alkenes have been realized. Dimeric cinchona alkaloids are the most frequently used catalysts in asymmetric halofunctionalizations. Most other catalysts have an appended functional group on the C9 position of the cinchona alkaloids. These functional groups include (thio)urea, thiocarbamate, and sulfonamides.
Redox‐Neutral α,β‐Difunctionalization of Cyclic Amines
Authors: Chen Weijie , Kang YoungKu , Wilde Richard G. , Seidel Daniel 
Published: April 2014

AbstractIn contrast to the continuously growing number of methods that allow for the efficient α‐functionalization of amines, few strategies exist that enable the direct functionalization of amines in the β‐position. A general redox‐neutral strategy is outlined for amine β‐functionalization and α,β‐difunctionalization that utilizes enamines generated in situ. This concept is demonstrated in the context of preparing polycyclic N,O‐acetals from simple 1‐(aminomethyl)‐β‐naphthols and 2‐(aminomethyl)‐phenols.
A Molecular Ferroelectric Thin Film of Imidazolium Perchlorate That Shows Superior Electromechanical Coupling
Authors: Zhang Yi , Liu Yuanming , Ye Heng‐Yun , Fu Da‐Wei , Gao Wenxiu , Ma He , Liu Zhiguo , Liu Yunya , Zhang Wen , Li Jiangyu , Yuan Guo‐Liang , Xiong Ren‐Gen 
Published: April 2014

AbstractMolecular ferroelectric thin films are highly desirable for their easy and environmentally friendly processing, light weight, and mechanical flexibility. A thin film of imidazolium perchlorate processed from aqueous solution is an excellent molecular ferroelectric with high spontaneous polarization, high Curie temperature, low coercivity, and superior electromechanical coupling. These attributes make it a molecular alternative to perovskite ferroelectric films in sensing, actuation, data storage, electro‐optics, and molecular/flexible electronics.
Substrate Templating Guides the Photoinduced Reaction of C60 on Calcite
Authors: Lindner Robert , Rahe Philipp , Kittelmann Markus , Gourdon André , Bechstein Ralf , Kühnle Angelika 
Published: April 2014

AbstractA substrate‐guided photochemical reaction of C60 fullerenes on calcite, a bulk insulator, investigated by non‐contact atomic force microscopy is presented. The success of the covalent linkage is evident from a shortening of the intermolecular distances, which is clearly expressed by the disappearance of the moiré pattern. Furthermore, UV/Vis spectroscopy and mass spectrometry measurements carried out on thick films demonstrate the ability of our setup for initiating the photoinduced reaction. The irradiation of C60 results in well‐oriented covalently linked domains. The orientation of these domains is dictated by the lattice dimensions of the underlying calcite substrate. Using the lattice mismatch to deliberately steer the direction of the chemical reaction is expected to constitute a general design principle for on‐surface synthesis. This work thus provides a strategy for controlled fabrication of oriented, covalent networks on bulk insulators.
Relationship of Gene Expression in the Injured Human Meniscus to Body Mass Index: A Biologic Connection Between Obesity and Osteoarthritis
Authors: Rai Muhammad Farooq , Patra Debabrata , Sandell Linda J. , Brophy Robert H. 
Published: April 2014

ObjectiveHigher body mass index (BMI) increases the risk of meniscus injury and knee osteoarthritis (OA). However, it is unknown if and how obesity affects meniscus biology. We analyzed transcriptome‐wide gene expression profiles of injured human menisci to test the hypothesis that meniscal gene expression signatures relate to patient BMI.MethodsMeniscus samples were obtained from patients undergoing arthroscopic partial meniscectomy. Transcriptome‐wide analysis of gene expression followed by validation of selected transcripts by QuantiGene Plex assay was performed. Correlations of gene expression with BMI and relative fold changes (≥1.5‐fold) in 3 BMI categories (lean [BMI 18.5–24.9 kg/m2], overweight [BMI 25.0–29.9 kg/m2], and obese [BMI >30.0 kg/m2]) were analyzed, and integrated functional classifications were probed computationally.ResultsThe obese versus overweight comparison resulted in the largest set of differences (565 transcripts) followed by obese versus lean (280 transcripts) and overweight versus lean (125 transcripts). Biologic reproducibility was confirmed by cluster analysis of expressed transcripts. Differentially regulated transcripts represented important functional classifications. Transcripts associated with oxygen transport, calcium ion binding, and cell homeostasis were elevated with BMI, while those related to extracellular matrix deposition, cell migration, and glucosamine metabolic processes were repressed. While these functional classifications may play key roles in cartilage/meniscus homeostasis, failure of extracellular matrix deposition and increase in calcium ion binding likely contribute to OA development following meniscal injury.ConclusionOur results indicate greater differences in gene expression between obese and overweight groups than between overweight and lean groups. This may indicate that there is a weight threshold at which injured meniscus responds severely to increased BMI. BMI‐related changes in gene expression present a plausible explanation for the role of meniscal injury in OA development among obese patients.
HLA–B27 Subtype Oligomerization and Intracellular Accumulation Patterns Correlate With Predisposition to Spondyloarthritis
Authors: Jeanty Cindy , Sourisce Adèle , Noteuil Aurélie , Jah Nadège , Wielgosik Aurore , Fert Ingrid , Breban Maxime , André Claudine 
Published: April 2014

ObjectiveMechanisms underlying the striking association of spondyloarthritis (SpA) with the class I major histocompatibility complex molecule HLA–B27 remain poorly understood. SpA‐like disease develops spontaneously in B*2705‐transgenic rats, in conjunction with high HLA–B27 expression levels. This study was undertaken to examine the effects of increased expression of HLA–B27 alleles that are differentially associated with SpA on oligomerization and intracellular redistribution.MethodsHeLa cells were transfected with complementary DNA encoding for HLA–B proteins fused to yellow fluorescent protein and/or Renilla luciferase and harvested at an early phase and a later phase of expression. We monitored HLA–B intracellular trafficking and localization by means of microscopy and live‐cell imaging. Bioluminescence resonance energy transfer (BRET) and Western blotting were used to monitor HLA–B oligomerization.ResultsAt low expression levels, BRET signals were similarly elevated for all SpA‐associated HLA–B27 alleles tested, but were lower for the nonassociated B*2706. Of note, at higher expression levels, HLA–B27 signals remained steady while signal for HLA–B7 decreased sharply, reaching the level observed for B*2706. This was due at least in part to a decreased oligomer proportion without unfolded protein response outbreak. Such differential behavior was not abrogated by proteasome inhibition. With increased expression, all HLA–B proteins accumulated to a high density in cytoplasmic vesicles with labile form and size. The extent of this phenomenon was closely correlated with the level of association with predisposition to SpA.ConclusionTo our knowledge, this is the first report of a correlation between the level of predisposition to SpA conferred by HLA–B27 alleles and their biochemical behavior. These findings open new perspectives for understanding the pathogenicity of HLA–B27.
Deletion of the Antiphospholipid Syndrome Autoantigen β2‐Glycoprotein I Potentiates the Lupus Autoimmune Phenotype in a Toll‐like Receptor 7–Mediated Murine Model
Authors: Giannakopoulos Bill , Mirarabshahi Peyman , Qi Miao , Weatherall Chris , Qi Jian Cheng , Tanaka Kumiko , Millar Ewan , Vonthethoff Leon , Gatto Dominique , Spielman Derek , Krilis Steven A. 
Published: April 2014

ObjectiveThe BXSB.Yaa mouse strain is a model of systemic lupus erythematosus that is dependent on duplication of the Toll‐like receptor 7 gene. The objective of this study was to systematically describe the amplified autoimmune phenotype observed when the soluble plasma protein β2‐glycoprotein I (β2GPI) gene was deleted in male BXSB.Yaa mice.MethodsWe generated BXSB.Yaa and NZW mouse strains in which the β2GPI gene had been knocked out by backcrossing the wild‐type strains with C57BL/6 β2GPI−/− mice for 10 generations. Sex‐ and age‐matched mice of the various strains were housed under identical conditions and were killed at fixed time intervals. Serum and tissue specimens were collected at various time points. Lupus‐associated autoantibodies, inflammatory cytokines, and the type I interferon (IFN) gene signature were measured. Flow cytometric analyses of lymphocyte populations were performed. The severity of glomerulonephritis was graded by 2 independent renal histopathologists.ResultsMale BXSB.Yaa β2GPI−/− mice developed significant lymphadenopathy and splenomegaly compared with age‐matched controls. Male BXSB.Yaa β2GPI−/− mice also had significantly higher levels of autoantibodies, increased levels of inflammatory cytokines including tumor necrosis factor α, interleukin‐6, and BAFF, and more severe glomerulonephritis. The type I IFN gene signature in male BXSB.Yaa β2GPI−/− mice was significantly higher than that in control mice. Male BXSB.Yaa β2GPI−/− mice also had marked dysregulation of various B cell and T cell populations in the spleens and lymph nodes and a disturbance in apoptotic cell clearance.ConclusionDeletion of β2GPI accelerates and potentiates the autoimmune phenotype in male BXSB.Yaa mice.
Brief Report: T Cell Expression of Granulocyte–Macrophage Colony‐Stimulating Factor in Juvenile Arthritis Is Contingent Upon Th17 Plasticity
Authors: Piper Christopher , Pesenacker Anne M. , Bending David , Thirugnanabalan Balathas , Varsani Hemlata , Wedderburn Lucy R. , Nistala Kiran 
Published: April 2014

ObjectiveGranulocyte–macrophage colony stimulating factor (GM‐CSF) is a potent inflammatory mediator that is responsible for recruitment and activation of innate immune cells. Recent data from murine studies have identified Th17 cells as a key source of GM‐CSF and suggest that T cell–derived GM‐CSF is instrumental in the induction of autoimmune disease. The present study was undertaken to analyze the expression of T cell–derived GM‐CSF in the joints of patients with juvenile idiopathic arthritis (JIA) and to investigate the differentiation of Th17 cells and how this relates to GM‐CSF+ T helper cells.MethodsSynovial fluid (SF) and peripheral blood (PB) samples from 24 patients with JIA were analyzed, by flow cytometry and reverse transcription–polymerase chain reaction, for expression of GM‐CSF and the Th17 marker CD161. A cytokine capture assay was used to purify Th17 cells and test the plasticity of cytokine production in response to interleukin‐12 (IL‐12) and IL‐23.ResultsThe frequency of GM‐CSF–producing T helper cells was significantly enriched in SF mononuclear cells compared to PB mononuclear cells from the patients with JIA (24.1% of CD4+ T cells versus 2.9%) and closely correlated with the erythrocyte sedimentation rate (r2 = 0.91, P < 0.001). Synovial GM‐CSF+ T cells were predominantly CD161+ and coexpressed interferon‐γ (IFNγ), but not IL‐17. Culture of Th17 cells in the presence of IL‐12 led to rapid up‐regulation of GM‐CSF and IFNγ, recapitulating the phenotype of GM‐CSF–expressing cells within the joint.ConclusionOur results identify a novel outcome of Th17 plasticity in humans that may account for the enrichment of GM‐CSF–expressing T cells in the joints of patients with JIA. The association of GM‐CSF expression with systemic inflammation highlights the potential role of Th17‐related cytokines in the pathology of JIA.
Fucosyltransferase 1 Mediates Angiogenesis in Rheumatoid Arthritis
Authors: Isozaki Takeo , Amin Mohammad A. , Ruth Jeffrey H. , Campbell Phillip L. , Tsou Pei‐Suen , Ha Christine M. , Stinson W. Alex , Domino Steven E. , Koch Alisa E. 
Published: April 2014

ObjectiveTo determine the role of α(1,2)‐linked fucosylation of proteins by fucosyltransferase 1 (FUT1) in rheumatoid arthritis (RA) angiogenesis.MethodsAnalysis of α(1,2)‐linked fucosylated proteins in synovial tissue (ST) samples was performed by immunohistologic staining. Expression of α(1,2)‐linked fucosylated angiogenic chemokine in synovial fluid (SF) was determined by immunoprecipitation and lectin blotting. To determine the angiogenic role of α(1,2)‐linked fucosylated proteins in RA, we performed human dermal microvascular endothelial cell (HMVEC) chemotaxis and Matrigel assays using sham‐depleted and α(1,2)‐linked fucosylated protein–depleted RA SF samples. To examine the production of proangiogenic chemokines by FUT1 in HMVECs, cells were transfected with FUT1 sense or antisense oligonucleotides, and enzyme‐linked immunosorbent assay was performed. We then studied mouse lung endothelial cell (EC) chemotaxis using wild‐type and FUT1 gene–deficient mouse lung ECs.ResultsRA ST endothelial cells showed high expression of α(1,2)‐linked fucosylated proteins compared to normal ST. The expression of α(1,2)‐linked fucosylated monocyte chemoattractant protein 1 (MCP‐1)/CCL2 was significantly elevated in RA SF compared with osteoarthritis SF. Depletion of α(1,2)‐linked fucosylated proteins in RA SF induced less HMVEC migration and tube formation than occurred in sham‐depleted RA SF. We found that blocking FUT1 expression in ECs resulted in decreased MCP‐1/CCL2 and RANTES/CCL5 production. Finally, we showed that FUT1 regulates EC migration in response to vascular endothelial cell growth factor.ConclusionOur findings indicate that α(1,2)‐linked fucosylation by FUT1 may be an important new target for angiogenic diseases such as RA.
Genome‐Wide Copy Number Variation Analysis Identifies Deletion Variants Associated With Ankylosing Spondylitis
Authors: Jung Seung‐Hyun , Yim Seon‐Hee , Hu Hae‐Jin , Lee Kyu Hoon , Lee Joo‐Hyun , Sheen Dong‐Hyuk , Lim Mi‐Kyoung , Kim Soon‐Young , Park Sung‐Won , Kim So‐Hee , Han Kyudong , Kim Tae‐Hwan , Shim Seung‐Cheol , Chung Yeun‐Jun 
Published: April 2014

ObjectiveTo identify ankylosing spondylitis (AS)–associated copy number variations (CNVs) in Korean subjects and their synergistic roles in the development of AS.MethodsA genome‐wide association study (GWAS) was performed in 309 patients with AS and 309 control subjects, using a copy number variant (CNV) microarray. AS‐associated CNV regions were replicated in 2 independent sets (625 patients and 891 control subjects) by quantitative polymerase chain reaction (PCR) and deletion‐typing PCR.ResultsIn the CNV GWAS, 227 CNV regions were shown to be significantly associated with the risk of AS. Of the candidate CNV regions, 9 were successfully replicated in the first replication analysis: 1q32.2 (HHAT), 1p34.2 (BMP8A), 2q31.2 (PRKRA), 6p21.32 (HLA–DPB1), 11q22.1 (CNTN5), 13q13.1 (EEF1DP3), 14q24.2 (RGS6), 16p13.3, and 22q11.1 (IL17RA). The 5 deletion‐type CNV regions, in 1q32.2, 2q31.2, 6p21.32, 13q13.1, and 16p13.3, were associated with an increased risk of AS, and the other 4 CNV regions were protective. In the second replication analysis, 4 CNV regions in 1q32.2, 2q31.2, 6p21.32, and 16p13.3 were replicated. Among patients with CNV regions in ≥4 risk‐increasing loci, the risk was 18.0 times higher than that in patients without any deletions (odds ratio [OR] 17.98, P = 2.3 × 10−7). Among patients with CNV regions in ≥2 protective loci, the risk was 5.2 times lower than that in those without any deletions (OR 0.19, P = 4.0 × 10−10). The additive effects of simultaneous events were shown to be dependent on the frequency of CNV regions. Through deletion‐typing PCR and sequencing, the exact sizes and breakpoint sequences were defined in 4 CNV regions. The mechanism of all 3 deletions was shown to be microhomology‐based nonhomologous end joining.ConclusionThe results of this study can help to identify pathogenic mechanisms of AS and can easily be applied in the development of algorithms estimating the risk of AS.
Effect of Methotrexate Use and Erythrocyte Methotrexate Polyglutamate on Glycosylated Hemoglobin in Rheumatoid Arthritis
Authors: de Rotte Maurits C. F. J. , de Jong Pascal H. P. , den Boer Ethan , Pluijm Saskia M. F. , Özcan Behiye , Weel Angelique E. A. M. , Lindemans Jan , Hazes Johanna M. W. , de Jonge Robert 
Published: April 2014

ObjectiveTo investigate whether methotrexate (MTX) use, as compared to other therapies, and erythrocyte methotrexate polyglutamate (MTXGlu) concentrations are associated with changes in glycosylated hemoglobin (HbA1c) levels in rheumatoid arthritis (RA) patients.MethodsThe derivation cohort consisted of patients selected from the Treatment in the Rotterdam Early Arthritis Cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. Patients were randomized to 6 treatment arms: triple disease‐modifying antirheumatic drug (DMARD) therapy (consisting of MTX, sulfasalazine, and hydroxychloroquine [HCQ]) + intramuscular (IM) glucocorticoids, triple DMARD therapy + oral glucocorticoids, MTX + oral glucocorticoid therapy, MTX therapy, oral glucocorticoid therapy, and HCQ therapy. HbA1c levels were determined at baseline and at 3 months. Concentrations of erythrocyte MTXGlu1–5 were measured after 3 months of treatment. Within treatment arms, changes in the level of HbA1c were compared by paired t‐test. Associations of MTXGlu concentrations with changes in the level of HbA1c were tested using multiple linear regression analysis, adjusted for age, sex, body mass index, and comedication. Significant associations were validated using data on RA patients taking MTX who were enrolled in the Methotrexate in Rotterdam cohort.ResultsIn the derivation cohort, the mean change in HbA1c level after 3 months of treatment was −1.9 mmoles/mole (−0.18%) (P = 0.001). Levels of HbA1c decreased in 4 of the individual treatment groups, as follows: for the triple DMARD therapy + IM glucocorticoids treatment arm, −5.5 mmoles/mole (−0.50%) (P < 0.001), for the triple DMARD therapy + oral glucocorticoids treatment arm, –3.7 mmoles/mole (−0.34%) (P < 0.001), for the MTX treatment arm, −0.8 mmoles/mole (−0.08%) (P = 0.018), and for the HCQ treatment arm, −2.0 mmoles/mole (−0.19%) (P = 0.175). Increased levels of MTXGlu2 (β = −0.20, P = 0.005), MTXGlu3 (β = −0.31, P < 0.001), MTXGlu4 (β = −0.33, P < 0.001) after treatment, MTXGlu5 (β = −0.39, P < 0.001), and total MTXGlu (β = −0.29, P < 0.001) were associated with decreased levels of HBA1c. In the validation cohort, levels of HbA1c were decreased by 2.6 mmoles/mole (0.23%) (P < 0.001) after treatment, and MTXGlu3 was associated with decreased levels of HbA1c (β = −0.26, P = 0.018).ConclusionMTX use and higher concentrations of erythrocyte MTXGlu are associated with decreased levels of HbA1c in RA patients. Triple DMARD therapy and HCQ treatment resulted in reduced HbA1c levels, and glucocorticoid treatment resulted in increased levels of HbA1c.