bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence of Severe Infections and Infection‐Related Mortality During the Course of Giant Cell Arteritis: A Multicenter, Prospective, Double‐Cohort Study
Authors: Schmidt J. , Smail A. , Roche B. , Gay P. , Salle V. , Pellet H. , Duhaut P. 
Published: January 2016

ObjectiveTo assess the incidence of infections leading to hospitalization, the mortality rate related to infections, and the determinants of these factors in patients with giant cell arteritis (GCA).MethodsIn total, 486 patients with GCA (75% women) were enrolled at the time of diagnosis. All patients fulfilled the American College of Rheumatology criteria for GCA. As controls, age‐ and sex‐matched subjects were randomly selected from the general population and matched to patients at the time of diagnosis of GCA. Both groups were prospectively followed up over a 5‐year period.ResultsSevere infections were more frequent among patients with GCA during the first year after diagnosis, compared to general population controls (incidence rate ratio 2.1, 95% confidence interval [95% CI] 1.2–3.4; incidence rate 11.1/100 patient‐years [95% CI 8.3–14.6] in patients with GCA versus 5.9/100 patient‐years [95% CI 4–8.4] in controls). Specifically, septic shock and infectious colitis were more frequent among the patients with GCA. Mortality caused by infections was higher in patients with GCA compared to controls (P < 0.0001 by log rank test). In analyses adjusted for age, among patients with GCA, a diagnosis of diabetes (hazard ratio [HR] 3.3, 95% CI 1.4–7.7) and a corticosteroid dosage that was >10 mg/day after 12 months of treatment (HR 4.61, 95% CI 1.38–15.36) were associated with death attributed to severe infection. The observed overall incidence of mortality was increased in patients with GCA during the early period of enrollment in the study (before 1997) (P = 0.0001 by log rank test), but thereafter was the same as that in the general population controls.ConclusionFrequencies of severe infections and rates of infection‐related mortality are increased during the first year after the diagnosis of GCA. The risk of infection increases in GCA patients with older age or in the presence of diabetes, or is greater when the dosage of corticosteroids has been increased to >10 mg/day after 12 months of treatment.
Regulation of Effector Treg Cells in Murine Lupus
Authors: Chandrasekaran Uma , Yi Woelsung , Gupta Sanjay , Weng Chien‐Huan , Giannopoulou Eugenia , Chinenov Yurii , Jessberger Rolf , Weaver Casey T. , Bhagat Govind , Pernis Alessandra B. 
Published: January 2016

ObjectiveTreg cells need to acquire an effector phenotype to function in settings of inflammation. Whether effector Treg cells can limit disease severity in lupus is unknown. Interferon regulatory factor 4 (IRF‐4) is an essential controller of effector Treg cells and regulates their ability to express interleukin‐10 (IL‐10). In non–Treg cells, IRF‐4 activity is modulated by interactions with DEF‐6 and its homolog switch‐associated protein 70 (SWAP‐70). Although mice lacking both DEF‐6 and SWAP‐70 (double‐knockout [DKO] mice) develop lupus, they display normal survival, suggesting that in DKO mice, Treg cells can moderate disease development. The purpose of this study was to investigate whether Treg cells from DKO mice have an increased capacity to become effector Treg cells due to the ability of DEF‐6 and SWAP‐70 to restrain IRF‐4 activity.MethodsTreg cells were evaluated by fluorescence‐activated cell sorting. The B lymphocyte–induced maturation protein 1 (BLIMP‐1)/IL‐10 axis was assessed by crossing DKO mice with BLIMP‐1‐YFP‐10BiT dual‐reporter mice. Deletion of IRF‐4 in Treg cells from DKO mice was achieved by generating FoxP3CreIRF‐4fl/fl DKO mice.ResultsThe concomitant absence of DEF‐6 and SWAP‐70 led to increased numbers of Treg cells, which acquired an effector phenotype in a cell‐intrinsic manner. In addition, Treg cells from DKO mice exhibited enhanced expression of the BLIMP‐1/IL‐10 axis. Notably, DKO effector Treg cells survived and expanded as disease progressed. The accumulation of Treg cells from DKO mice was associated with the up‐regulation of genes controlling autophagy. IRF‐4 was required for the expansion and function of effector Treg cells from DKO mice.ConclusionThis study revealed the existence of mechanisms that, by acting on IRF‐4, can fine‐tune the function and survival of effector Treg cells in lupus. These findings suggest that the existence of a powerful effector Treg cell compartment that successfully survives in an unfavorable inflammatory environment could limit disease development.
Association of Alterations in Gray Matter Volume With Reduced Evoked‐Pain Connectivity Following Short‐Term Administration of Pregabalin in Patients With Fibromyalgia
Authors: Puiu Tudor , Kairys Anson E. , Pauer Lynne , Schmidt‐Wilcke Tobias , Ichesco Eric , Hampson Johnson P. , Napadow Vitaly , Clauw Daniel J. , Harris Richard E. 
Published: January 2016

ObjectivePregabalin (PGB) is an α2δ calcium‐channel subunit ligand that has previously been shown to reduce chronic pain in multiple conditions. Preclinical studies indicate that PGB may down‐regulate brain glutamate release while also inhibiting astrocyte induction of glutamatergic synapse formation, and recent clinical findings support the notion that PGB modulates glutamatergic activity and functional brain connectivity in order to produce analgesia. The present study was undertaken to examine concurrent changes in brain gray matter volume (GMV) or evoked‐pain connectivity in humans receiving PGB.MethodsSixteen female fibromyalgia patients participated in a randomized double‐blind 2‐period crossover study of PGB versus placebo. Before and after each period, patients underwent high‐resolution structural and evoked pressure–pain functional brain imaging. GMV was analyzed using voxel‐based morphometry, and functional connectivity during evoked pressure–pain was assessed.ResultsPGB administration significantly reduced GMV within the posterior insula bilaterally, whereas there were no significant changes in insular GMV following placebo treatment. GMV reductions in the medial frontal gyrus were also observed when comparing PGB versus placebo treatment, and were associated with reduced clinical pain. These reductions in insular GMV were associated with concomitant reductions in connectivity to the default mode network, which was also associated with reduced clinical pain.ConclusionShort‐term PGB treatment altered brain structure and evoked‐pain connectivity, and these decreases were associated with reduced clinical pain. We speculate that these fairly rapid changes in GMV may be related to brain neuroplasticity. It is unknown whether these effects are generalizable to other chronic pain states.
Next‐Generation Sequencing Reveals Restriction and Clonotypic Expansion of Treg Cells in Juvenile Idiopathic Arthritis
Authors: Henderson Lauren A. , Volpi Stefano , Frugoni Francesco , Janssen Erin , Kim Susan , Sundel Robert P. , Dedeoglu Fatma , Lo Mindy S. , Hazen Melissa M. , Beth Son Mary , Mathieu Ronald , Zurakowski David , Yu Neng , Lebedeva Tatiana , Fuhlbrigge Robert C. , Walter Jolan E. , Nee Lee Yu , Nigrovic Peter A. , Notarangelo Luigi D. 
Published: January 2016

ObjectiveTreg cell–mediated suppression of Teff cells is impaired in juvenile idiopathic arthritis (JIA); however, the basis for this dysfunction is incompletely understood. Animal models of autoimmunity and immunodeficiency demonstrate that a diverse Treg cell repertoire is essential to maintain Treg cell function. The present study was undertaken to investigate the Treg and Teff cell repertoires in JIA.MethodsTreg cells (CD4+CD25+CD127low) and Teff cells (CD4+CD25−) were isolated from peripheral blood and synovial fluid obtained from JIA patients, healthy controls, and children with Lyme arthritis. Treg cell function was measured in suppressive assays. The T cell receptor β chain (TRB) was amplified by multiplex polymerase chain reaction and next‐generation sequencing was performed, with amplicons sequenced using an Illumina HiSeq platform. Data were analyzed using ImmunoSEQ, International ImMunoGeneTics system, and the Immunoglobulin Analysis Tools.ResultsCompared to findings in controls, the JIA peripheral blood Treg cell repertoire was restricted, and clonotypic expansions were found in both blood and synovial fluid Treg cells. Skewed usage and pairing of TRB variable and joining genes, including overuse of gene segments that have been associated with other autoimmune conditions, was observed. JIA patients shared a substantial portion of synovial fluid Treg cell clonotypes that were private to JIA and not identified in Lyme arthritis.ConclusionWe identified restriction and clonotypic expansions in the JIA Treg cell repertoire with sharing of Treg cell clonotypes across patients. These findings suggest that abnormalities in the Treg cell repertoire, possibly engendered by shared antigenic triggers, may contribute to disease pathogenesis in JIA.
Distinct Functions of Autoantibodies Against Interferon in Systemic Lupus Erythematosus: A Comprehensive Analysis of Anticytokine Autoantibodies in Common Rheumatic Diseases
Authors: Gupta Sarthak , Tatouli Ioanna P. , Rosen Lindsey B. , Hasni Sarfaraz , Alevizos Ilias , Manna Zerai G. , Rivera Juan , Jiang Chao , Siegel Richard M. , Holland Steven M. , Moutsopoulos Haralampos M. , Browne Sarah K. 
Published: January 2016

ObjectiveAnticytokine autoantibodies occur across a range of hematologic, pulmonary, and infectious diseases. However, systematic investigation of their presence and significance in autoimmune diseases is lacking. This study was undertaken to examine the distinct functions of anticytokine autoantibodies in patients with systemic lupus erythematosus (SLE) compared to patients with other rheumatic diseases and healthy controls.MethodsSerum samples from patients with SLE (n = 199), patients with primary Sjögren's syndrome (SS) (n = 150), patients with rheumatoid arthritis (RA) (n = 149), and healthy controls (n = 200) were screened for 24 anticytokine autoantibodies using a multiplex bead‐based assay. To evaluate the biologic activity of anticytokine autoantibodies, their ability to block cytokine‐induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in a subset of healthy controls and patients with SLE.ResultsPatients with SLE and those with SS had a striking excess of autoantibodies against interferons and the interferon‐responsive chemokine interferon‐inducible protein 10 (IP‐10). Only autoantibodies against type I interferon, interleukin‐12 (IL‐12), and IL‐22 exhibited neutralizing activity. In SLE, the presence of anti–interferon‐γ autoantibodies was correlated with more severe disease activity, higher levels of anti–double‐stranded DNA antibodies, and elevated expression of interferon‐α/β–inducible genes. Conversely, in SLE patients with blocking anti–interferon‐α autoantibodies, the type I interferon gene expression signature was normalized. Anti–type III interferon autoantibodies (λ2, λ3) and anti–IP‐10 autoantibodies were newly recognized in SLE patient serum, and autoantibodies against macrophage‐colony stimulating factor, IL‐4, IL‐7, IL‐17, and IL‐22, none of which have been previously identified in rheumatic conditions, were discovered.ConclusionAnticytokine autoantibodies are associated with distinct patterns of disease in SLE, SS, and RA. Anti‐interferon autoantibodies are overrepresented in patients with SLE and those with SS, and fall into distinct functional classes, with only a subset of anti–type I interferon antibodies exhibiting neutralizing activity. Anti–interferon‐γ autoantibodies are correlated with increased disease activity and interferon‐related gene expression, suggesting that such autoantibodies may contribute to the pathogenesis of SLE.
Brief Report: Spatial Heterogeneity of Systemic Sclerosis in France: High Prevalence in the Northeast Region
Authors: Meyer Alain , Chifflot Hélène , Chatelus Emmanuel , Kleinmann Jean‐François , Ronde‐Ousteau Cécile , Klein Delphine , Jégu Jérémy , Geny Bernard , Hirshi Sandrine , Canuet Matthieu , Blaison Gilles , Kieffer Pierre , Lipsker Dan , Martin Thierry , Sauleau Erik , Velten Michel , Sibilia Jean 
Published: January 2016

ObjectiveAlsace is a region in eastern France with a population of ∼2 million. All residents have high access to health care and an accredited referral center for SSc. Seeking care outside of this region is difficult because of the peculiar geography. The aim of this study was to assess the prevalence and spatial variation of systemic sclerosis (SSc) in eastern France.MethodsData for SSc patients were obtained from 3 sources (all general practitioners and community specialists, capillaroscopy centers, and all public and private hospital records) and were used to estimate the prevalence of SSc. Surviving patients who resided in Alsace on January 1, 2008 and fulfilled the American College of Rheumatology and/or the LeRoy and Medsger criteria were included in this study. The clinical characteristics of the patients were also assessed. Potentially incomplete case ascertainment was corrected by capture–recapture analyses. Geographic disparities were assessed by spatial cluster analysis and by comparing our results with those for other geographic areas in the world for which data derived using similar methodology were available.ResultsThe review of 499 potential cases identified a total of 244 SSc patients. A trend toward a west‐to‐east gradient was observed but did not reach statistical significance. According to log‐linear modeling, an estimated 83.87 additional cases were missed. Thus, the SSc prevalence was 228.42 cases per million adult inhabitants of Alsace (95% confidence interval 203.70–253.14); this prevalence was significantly higher than that in 2 other regions of France and comparable with the reported prevalence in Detroit, Michigan.ConclusionThe stringent methodology used in the current study is very likely to provide an accurate estimation of the prevalence of SSc. Design similarity with 3 other surveys extends the scope of the results by identifying geographic disparities that were previously indistinguishable due to methodologic differences.
Trends in Long‐Term Outcomes Among Patients With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis With Renal Disease
Authors: Rhee Rennie L. , Hogan Susan L. , Poulton Caroline J. , McGregor Julie Anne G. , Richard Landis J. , Falk Ronald J. , Merkel Peter A. 
Published: January 2016

ObjectiveIt is still not clear how advances in the management of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) have impacted long‐term outcomes. We undertook this study to examine changes over 25 years in long‐term clinical outcomes, including the impact of renal function at diagnosis (a potential marker of time to disease detection) and the duration of cyclophosphamide use in AAV patients with renal involvement.MethodsWe included ANCA‐positive patients with biopsy‐proven AAV diagnosed between 1985 and 2009 who were followed up in the Glomerular Disease Collaborative Network inception cohort. Outcomes included the composite outcome of end‐stage renal disease (ESRD) or death as well as relapse. Cox proportional hazards or competing risks regression models were adjusted for potential baseline confounders.ResultsData from 554 patients were included in the analysis. There was a decreasing 5‐year risk of ESRD or death over time (P < 0.001 by log rank test for trend). After adjustment for baseline characteristics, the risk of relapse was similar across the time periods (P = 0.45 by test for trend). Serum creatinine level at baseline was the only significant predictor of an increased risk of ESRD or death (hazard ratio 1.11 per 1 mg/dl of serum creatinine [95% confidence interval 1.04–1.18], P = 0.002).ConclusionIn patients with renal disease secondary to AAV, over 25 years the risk of ESRD or death has decreased but the risk of relapse has not changed. A higher serum creatinine level at diagnosis is associated with a higher risk of ESRD or death, suggesting that earlier disease detection is potentially an important measure to improve outcomes in AAV.
Detection of lysozyme with aptasensor based on fluorescence resonance energy transfer from carbon dots to graphene oxide
Authors: Wu Jing , Hou Yu , Wang Peiyao , Wang Zhenni , Li Yanjie , Wang Shan , Yang Mei 
Published: January 2016

AbstractA photoluminescent aptasensor has been developed for the detection of lysozyme based on fluorescence resonance energy transfer (FRET) between the carbon dots (CDs) and graphene oxide (GO). In the sensing system, the CDs‐labeled aptamer is adsorbed onto the GO surface and the photoluminescence (PL) signal of the CDs is effectively quenched by GO. Addition of lysozyme can cause a significant FRET inhibition and recover the PL signal of the CDs due to the specific combination of lysozyme and its aptamer and the removal of the CDs‐labeled aptamer from GO surface. Under optimal conditions, the ratio of PL intensity change at 440 nm of the sensing system before and after the addition of lysozyme shows a good linear relationship against the concentration of lysozyme in the range of 0.01–2 μg/mL, with a low detection limit of 1 × 10−3 μg/mL. In addition, the aptasensor has good selectivity so it can distinguish lysozyme with no or little interference by many other biomolecules. It was applied to the detection of lysozyme in human sera with satisfactory recoveries. The results demonstrate the applicability of the aptasensor for monitoring lysozyme in real samples. Copyright © 2016 John Wiley & Sons, Ltd.
Rapid ester biosynthesis screening reveals a high activity alcohol‐O‐acyltransferase (AATase) from tomato fruit
Authors: Lin Jyun‐Liang , Zhu Jie , Wheeldon Ian 
Published: January 2016

AbstractEthyl and acetate esters are naturally produced in various yeasts, plants, and bacteria. The biosynthetic pathways that produce these esters share a common reaction step, the condensation of acetyl/acyl‐CoA with an alcohol by alcohol‐O‐acetyl/acyltransferase (AATase). Recent metabolic engineering efforts exploit AATase activity to produce fatty acid ethyl esters as potential diesel fuel replacements as well as short‐ and medium‐chain volatile esters as fragrance and flavor compounds. These efforts have been limited by the lack of a rapid screen to quantify ester biosynthesis. Enzyme engineering efforts have also been limited by the lack of a high throughput screen for AATase activity. Here, we developed a high throughput assay for AATase activity and used this assay to discover a high activity AATase from tomato fruit, Solanum lycopersicum (Atf‐S.l). Atf1‐S.l exhibited broad specificity towards acyl‐CoAs with chain length from C4 to C10 and was specific towards 1‐pentanol. The AATase screen also revealed new acyl‐CoA substrate specificities for Atf1, Atf2, Eht1, and Eeb1 from Saccharomyces cerevisiae, and Atf‐C.m from melon fruit, Cucumis melo, thus increasing the pool of characterized AATases that can be used in ester biosynthesis of ester‐based fragrance and flavor compounds as well as fatty acid ethyl ester biofuels.
Functionalized silk assembled from a recombinant spider silk fusion protein (Z‐4RepCT) produced in the methylotrophic yeast Pichia pastoris
Authors: Jansson Ronnie , Lau Cheuk H , Ishida Takuya , Ramström Margareta , Sandgren Mats , Hedhammar My 
Published: January 2016

AbstractFunctional biological materials are a growing research area with potential applicability in medicine and biotechnology. Using genetic engineering, the possibility to introduce additional functions into spider silk‐based materials has been realized. Recently, a recombinant spider silk fusion protein, Z‐4RepCT, was produced intracellularly in Escherichia coli and could after purification self‐assemble into silk‐like fibers with ability to bind antibodies via the IgG‐binding Z domain. In this study, the use of the methylotrophic yeast Pichia pastoris for production of Z‐4RepCT has been investigated. Temperature, pH and production time were influencing the amount of soluble Z‐4RepCT retrieved from the extracellular fraction. Purification of secreted Z‐4RepCT resulted in a mixture of full‐length and degraded silk proteins that failed to self‐assemble into fibers. A position in the C‐terminal domain of 4RepCT was identified as being subjected to proteolytic cleavage by proteases in the Pichia culture supernatant. Moreover, the C‐terminal domain was subjected to glycosylation during production in P. pastoris. These observed alterations of the CT domain are suggested to contribute to the failure in fiber assembly. As alternative approach, Z‐4RepCT retrieved from the intracellular fraction, which was less degraded, was used and shown to retain ability to assemble into silk‐like fibers after enzymatic deglycosylation.
High‐throughput cell quantification assays for use in cell purification development – enabling technologies for cell production
Authors: Zimmermann Sarah , Gretzinger Sarah , Scheeder Christian , Schwab Marie‐Luise , Oelmeier Stefan A. , Osberghaus Anna , Gottwald Eric , Hubbuch Jürgen 
Published: January 2016

AbstractHigh‐throughput screening (HTS) technology is gaining increasing importance in downstream process development of cell‐based products. The development of such HTS‐technologies, however, is highly dependent on the availability of robust, accurate, and sensitive high‐throughput cell quantification methods. In this article, we compare state‐of‐the‐art cell quantification methods with focus on their applicability in HTS‐platforms for downstream processing of cell‐based products. Sensitivity, dynamic range, and precision were evaluated for four methods that differ in their respective mechanism. In addition, we evaluated the performance of these methods over a range of buffer compositions, medium densities, and viscosities, representing conditions found in many downstream processing methods. We found that CellTiter‐Glo™ and flow cytometry are excellent tools for high‐throughput cell quantification. Both methods have broad working ranges (3–4 log) and performed well over a wide range of buffer compositions. In comparison, CyQuant® Direct and CellTracker™ had smaller working ranges and were more sensitive to changes in buffer composition. For fast and sensitive quantification of a single cell type, CellTiter‐Glo™ performed best, while for more complex cell mixtures flow cytometry is the method of choice. Our analysis will facilitate the selection of the most suitable method for a specific application and provides a benchmark for future HTS development in downstream processing of cell‐based products.