bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophages and iron trafficking at the birth and death of red cells
Authors: Korolnek Tamara , Hamza Iqbal 
Published: March 2015

Abstract
Macrophages play a critical role in iron homeostasis via their intimate association with developing and dying red cells. Central nurse macrophages promote erythropoiesis in the erythroblastic island niche. These macrophages make physical contact with erythroblasts, enabling signaling and the transfer of growth factors and possibly nutrients to the cells in their care. Human mature red cells have a lifespan of 120 days before they become senescent and again come into contact with macrophages. Phagocytosis of red blood cells is the main source of iron flux in the body, because heme must be recycled from approximately 270 billion hemoglobin molecules in each red cell, and roughly 2 million senescent red cells are recycled each second. Here we will review pathways for iron trafficking found at the macrophage-erythroid axis, with a focus on possible roles for the transport of heme in toto.
Rheumatoid arthritis response to treatment across IgG1 allotype – anti-TNF incompatibility: a case-only study
Authors: Montes Ariana , Perez-Pampin Eva , Navarro-Sarabia Federico , Moreira Virginia , de la Serna Arturo Rodríguez , Magallares Berta , Vasilopoulos Yiannis , Sarafidou Theologia , Fernández-Nebro Antonio , Ordóñez María del Carmen , Narváez Javier , Cañete Juan D , Marquez Ana , Pascual-Salcedo Dora , Joven Beatriz , Carreira Patricia , Moreno-Ramos Manuel J , Caliz Rafael , Ferrer Miguel Angel , Garcia-Portales Rosa , Blanco Francisco J , Magro Cesar , Raya Enrique , Valor Lara , Alegre-Sancho Juan J , Balsa Alejandro , Martin Javier , Plant Darren , Isaacs John , Morgan Ann W , Barton Anne , Wilson Anthony G ,   on behalf of Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), Gómez-Reino Juan J , Gonzalez Antonio 
Published: March 2015

Abstract
Introduction
We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA).

Methods
The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria.

Results
An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication.

Conclusions
Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA.
Identification of NF-κB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis
Authors: Arismendi Maria , Giraud Matthieu , Ruzehaji Nadira , Dieudé Philippe , Koumakis Eugenie , Ruiz Barbara , Airo Paolo , Cusi Daniele , Matucci-Cerinic Marco , Salvi Erika , Cuomo Giovanna , Hachulla Eric , Diot Elisabeth , Caramaschi Paola , Riccieri Valeria , Avouac Jérôme , Kayser Cristiane , Allanore Yannick 
Published: March 2015

Abstract
Introduction
Systemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility.

Methods
Sixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy).

Results
We observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, Padj = 7.22 × 10−5), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, Padj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, Padj = 2.49 × 10−4) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (Padj = 4.45 × 10−4 and Padj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (Padj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10−4) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele.

Conclusions
An analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility.
Multiplex cytokine analysis of dermal interstitial blister fluid defines local disease mechanisms in systemic sclerosis
Authors: Clark Kristina EN , Lopez Henry , Abdi Bahja Ahmed , Guerra Sandra G , Shiwen Xu , Khan Korsa , Etomi Oseme , Martin George R , Abraham David J , Denton Christopher P , Stratton Richard J 
Published: March 2015

Abstract
Introduction
Clinical diversity in systemic sclerosis (SSc) reflects multifaceted pathogenesis and the effect of key growth factors or cytokines operating within a disease-specific microenvironment. Dermal interstitial fluid sampling offers the potential to examine local mechanisms and identify proteins expressed within lesional tissue. We used multiplex cytokine analysis to profile the inflammatory and immune activity in the lesions of SSc patients.

Methods
Dermal interstitial fluid sample from the involved forearm skin, and synchronous plasma samples were collected from SSc patients (n = 26, diffuse cutaneous SSc (DcSSc) n = 20, limited cutaneous SSc (LcSSc) n = 6), and healthy controls (HC) (n = 10) and profiled by Luminex® array for inflammatory cytokines, chemokines, and growth factors.

Results
Luminex® profiling of the dermal blister fluid showed increased inflammatory cytokines (median interleukin ( IL)-6 in SSc 39.78 pg/ml, HC 5.51 pg/ml, p = 0.01, median IL-15 in SSc 6.27 pg/ml, HC 4.38 pg/ml, p = 0.03), chemokines (monocyte chemotactic protein (MCP)-3 9.81 pg/ml in SSc, 7.18 pg/ml HC, p = 0.04), and profibrotic growth factors (platelet derived growth factor (PDGF)-AA 10.38 pg/ml versus 6.94 pg/ml in HC, p = 0.03). In general dermal fluid and plasma cytokine levels did not correlate, consistent with predominantly local production of these factors within the dermal lesions, rather than leakage from the serum. In hierarchical clustering and network analysis IL-6 emerged as a key central mediator.

Conclusions
Our data confirm that an immuno-inflammatory environment and aberrant vascular repair are intimately linked to fibroblast activation in lesional skin in SSc. This non-invasive method could be used to profile disease activity in the clinic, and identifies key inflammatory or pro-fibrotic proteins that might be targeted therapeutically. Distinct subgroups of SSc may be defined that show innate or adaptive immune cytokine signatures.
Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells
Authors: Castellano Giuseppe , Cafiero Cesira , Divella Chiara , Sallustio Fabio , Gigante Margherita , Pontrelli Paola , De Palma Giuseppe , Rossini Michele , Grandaliano Giuseppe , Gesualdo Loreto 
Published: March 2015

Abstract
Introduction
Type I interferons are pivotal in the activation of autoimmune response in systemic lupus erythematous. However, the pathogenic role of interferon-alpha in patients affected by lupus nephritis remains uncertain. The aim of our study was to investigate the presence of a specific interferon signature in lupus nephritis and the effects of interferon-alpha at renal level.

Methods
We performed immunohistochemical analysis for MXA-protein and in situ hybridization to detect interferon-alpha signature and production in human lupus nephritis. Through microarray studies, we analyzed the gene expression profile of renal tubular epithelial cells, stimulated with interferon-alpha. We validated microarray results through real-time polymerase chain reaction, flow cytometry on renal tubular epithelial cells, and through immunohistochemical analysis and confocal microscopy on renal biopsies.

Results
Type I interferons signature was characterized by MXA-specific staining in renal tubular epithelial cells; in addition, in situ hybridization showed that renal tubular epithelial cells were the major producers of interferon-alpha, indicating a potential autocrine effect. Whole-genome expression profile showed interferon-alpha induced up-regulation of genes involved in innate immunity, protein ubiquitination and switching to immunoproteasome. In accordance with the in vitro data, class IV lupus nephritis showed up-regulation of the immunoproteasome subunit LMP7 in tubular epithelial cells associated with type I interferon signature.

Conclusions
Our data indicate that type I interferons might have a pathogenic role in lupus nephritis characterized by an autocrine effect of interferon-alpha on renal tubular epithelial cells. Therefore we hypothesize that inhibition of type I interferons might represent a therapeutic target to prevent tubulo-interstitial damage in patients with lupus nephritis.
Racial disparities in total ankle arthroplasty utilization and outcomes
Authors: Singh Jasvinder A , Ramachandran Rekha 
Published: March 2015

Abstract
Introduction
The objective of this study was to examine the racial disparities in total ankle arthroplasty (TAA) utilization and outcomes.

Methods
We used the National Inpatient Sample (NIS) to study the time-trends. Race was categorized as White and Black. Utilization rates were calculated for the U.S. general population per 100,000. Hospital length of stay, discharge disposition and mortality after TAA were assessed. We used the Cochran Armitage trend test to assess time-trends from 1998 to 2011 and chi-square test to compare TAA utilization. We used analysis of variance or chi-squared test to compare the characteristics of Whites and Blacks undergoing TAA and logistic regression to compare mortality, length of stay and discharge to home versus medical facility.

Results
The mean ages for Whites undergoing TAA were 62 years and for Blacks was 52 years. Significant racial disparities were noted in TAA utilization rates (/100,000) in 1998, 0.14 in Whites vs. 0.07 in Blacks (P < 0.0001; 2-fold) and in 2011, 1.17 in Whites vs. 0.33 in Blacks (P < 0.0001; 4-fold). Racial disparities in TAA utilization increased significantly from 1998 to 2011 (P < 0.0001). There was a trend towards statistical significance for the difference in the length of hospital stay in Blacks vs. Whites (52.9% vs. 44.3% with length of hospital stay higher than the median; P = 0.08). Differences in the proportion discharged to an inpatient medical facility after TAA, 16.6% Blacks vs. 13.4% Whites, were not significant (P = 0.36).

Conclusions
This study demonstrated significant racial disparities with lower TAA utilization and suboptimal outcomes in Blacks compared to Whites. Further studies are needed to understand the mediators of these disparities and to assess whether these mediators can be targeted to reduce racial disparities in TAA.
The metastatic tumor antigen 1-transglutaminase-2 pathway is involved in self-limitation of monosodium urate crystal-induced inflammation by upregulating TGF-β1
Authors: Yen Jia-Hau , Lin Ling-Chung , Chen Meng-Chi , Sarang Zsolt , Leong Pui-Ying , Chang I-Chang , Hsu Jeng-Dong , Chen Jiunn-Horng , Hsieh Yu-Fan , Pallai Anna , Köröskényi Krisztina , Szondy Zsuzsa , Tsay Gregory J 
Published: March 2015

Abstract
Introduction
Transglutaminase 2 (TG2), a protein crosslinking enzyme with multiple biochemical functions, has been connected to various inflammatory processes. In this study, the involvement of TG2 in monosodium urate (MSU) crystal-induced inflammation was studied.

Methods
Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) were performed to detect TG2 expression in synovial fluid mononuclear cells (SFMCs) and synovial tissue from patients with gouty arthritis. MSU crystal-exposed RAW264.7 mouse macrophages were analyzed for interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), transforming growth factor β1 (TGF-β1) and TG2 expression by RT-PCR and enzyme-linked immunosorbent assay (ELISA). TG2 small interfering (si)-RNA-mediated silencing and overexpression in RAW264.7 cells were used to evaluate the involvement of TG2 in resolving MSU crystal-induced inflammation. The role of metastatic tumor antigen 1 (MTA1), a master chromatin modifier, was investigated by MTA1 si-RNA-mediated knockdown. In addition, the inflammatory responses were followed in wild type and TG2 null mice after being challenged with MSU crystals in an in vivo peritonitis model.

Results
TG2 expression was up-regulated in the synovium tissue and SFMCs from patients with gouty arthritis. The levels of MTA1, TG2, TGF-β1, IL-1β and TNF-α mRNAs were consistently increased in MSU crystal-stimulated RAW264.7 cells. si-MTA1 impaired the basal, as well as the MSU crystal-induced expression of TG2 and TGF-β1, but increased that of IL-1β and TNF-α. TG2 overexpression dramatically suppressed MSU crystal-induced IL-1β and TNF-α, but significantly enhanced the TGF-β1 production. Neutralizing TGF-β antibodies or inhibition of the crosslinking activity of TG2 attenuated these effects. On the contrary, loss of TG2 resulted in a reduced TGF-β, but in an increased IL-1β and TNF-α production in MSU crystal-stimulated RAW264.7 cells and mouse embryonic fibroblasts (MEFs). MSU crystal-stimulated IL-1β production was Janus kinase 2 (JAK2)-signaling dependent and TG2-induced TGF-β suppressed the activity of it. Finally, TG2-deficient mice exhibited hyper inflammatory responses after being challenged with MSU crystals in an in vivo peritonitis model.

Conclusions
These findings reveal an inherent regulatory role of the MTA1-TG2 pathway in the self-limitation of MSU crystal-induced inflammation via positively regulating the levels of active TGF-β1 in macrophages that opposes the MSU crystal-induced JAK2-dependent pro-inflammatory cytokine formation.
Heterogeneous responses and cross reactivity between the major peanut allergens Ara h 1, 2,3 and 6 in a mouse model for peanut allergy
Authors: Smit Joost J , Pennings Maarten T , Willemsen Karina , van Roest Manon , van Hoffen Els , Pieters Raymond H 
Published: March 2015

AbstractBackgroundThe relative contribution and the relation between individual peanut allergens in peanut allergic responses is still matter of debate. We determined the individual contribution of peanut proteins to B, T cell and allergic effector responses in a mouse model for peanut allergy.MethodsMice were immunized and challenged by oral gavage with peanut protein extract or isolated allergens Ara h 1, 2, 3 and 6 followed by assessment of food allergic manifestations. In addition, T cell responses to the individual proteins were measured by an in vitro dendritic cell‐T cell assay.ResultsSensitization with the individual peanut proteins elicited IgE responses with specificity to the allergen used as expected. However, cross reactivity among Ara h 1, 2, 3 and 6 was observed. T cell re‐stimulations with peanut extract and individual peanut proteins also showed cross reactivity between Ara h 1, 2, 3 and 6. Despite the cross reactivity at the IgE level, only Ara h 2 and 6 were able to elicit mast cell degranulation after an oral challenge. However, after systemic challenge, Ara h 1, 2 and 6 and to lesser extent Ara h 3 were able to elicit anaphylactic responses.ConclusionsAra h 1, 2, 3 and 6 sensitize via the intra‐gastric route, but differ in their capacity to cause allergic effector responses. Interestingly, extensive cross reactivity at T cell and antibody level is observed among Ara h 1, 2, 3 and 6, which may have important implications for the diagnosis and therapy of peanut allergy. Awareness about the relative contribution of individual peanut allergens and cross reactivity between these allergens is of importance for current research in diagnostics and therapeutics for and the mechanism of peanut allergy.
Unique and Shared Metabolic Regulation in Clonal β-Cells and Primary Islets Derived From Rat Revealed by Metabolomics Analysis
Authors: Spégel Peter , Andersson Lotta E. , Storm Petter , Sharoyko Vladimir , Göhring Isabel , Rosengren Anders H. , Mulder Hindrik 
Published: March 2015

Abstract
As models for β-cell metabolism, rat islets are, to some extent, a, heterogeneous cell population stressed by the islet isolation procedure, whereas rat-derived clonal β-cells exhibit a tumor-like phenotype. To describe to what extent either of these models reflect normal cellular metabolism, we compared metabolite profiles and gene expression in rat islets and the INS-1 832/13 line, a widely used clonal β-cell model. We found that insulin secretion and metabolic regulation provoked by glucose were qualitatively similar in these β-cell models. However, rat islets exhibited a more pronounced glucose-provoked increase of glutamate, glycerol-3-phosphate, succinate, and lactate levels, whereas INS-1 832/13 cells showed a higher glucose-elicited increase in glucose-6-phosphate, alanine, isocitrate, and α-ketoglutarate levels. Glucose induced a decrease in levels of γ-aminobutyrate (GABA) and aspartate in rat islets and INS-1 832/13 cells, respectively. Genes with cellular functions related to proliferation and the cell cycle were more highly expressed in the INS-1 832/13 cells. Most metabolic pathways that were differentially expressed included GABA metabolism, in line with altered glucose responsiveness of GABA. Also, lactate dehydrogenase A, which is normally expressed at low levels in mature β-cells, was more abundant in rat islets than in INS-1 832/13 cells, confirming the finding of elevated glucose-provoked lactate production in the rat islets. Overall, our results suggest that metabolism in rat islets and INS-1 832/13 cells is qualitatively similar, albeit with quantitative differences. Differences may be accounted for by cellular heterogeneity of islets and proliferation of the INS-1 832/13 cells.
A Novel Population of Inner Cortical Cells in the Adrenal Gland That Displays Sexually Dimorphic Expression of Thyroid Hormone Receptor-β1
Authors: Huang Chen-Che Jeff , Kraft Cary , Moy Nicole , Ng Lily , Forrest Douglas 
Published: March 2015

AbstractThe development of the adrenal cortex involves the formation and then subsequent regression of immature or fetal inner cell layers as the mature steroidogenic outer layers expand. However, controls over this remodeling, especially in the immature inner layer, are incompletely understood. Here we identify an inner cortical cell population that expresses thyroid hormone receptor-β1 (TRβ1), one of two receptor isoforms encoded by the Thrb gene. Using mice with a Thrbb1 reporter allele that expresses lacZ instead of TRβ1, β-galactosidase was detected in the inner cortex from early stages. Expression peaked at juvenile ages in an inner zone that included cells expressing 20-α-hydroxysteroid dehydrogenase, a marker of the transient, so-called X-zone in mice. The β-galactosidase-positive zone displayed sexually dimorphic regression in males after approximately 4 weeks of age but persisted in females into adulthood in either nulliparous or parous states. T3 treatment promoted hypertrophy of inner cortical cells, induced some markers of mature cortical cells, and, in males, delayed the regression of the TRβ1-positive zone, suggesting that TRβ1 could partly divert the differentiation fate and counteract male-specific regression of inner zone cells. TRβ1-deficient mice were resistant to these actions of T3, supporting a functional role for TRβ1 in the inner cortex.
Combining low sampling frequency smartphone sensors and video for a Wearable Mobility Monitoring System
Authors: Wu Hui-Hsien , Lemaire Edward , Baddour Natalie 
Published: March 2015

A proof-of-concept Wearable Mobility Monitoring System (WMMS) was developed to identify daily activities and provide environmental context, using integrated BlackBerry Smartphone low sensor and video data. Integrated accelerometer data were used to identify mobility changes-of-state (CoS) in real-time, trigger BlackBerry video capture at each CoS, and save activity outcomes on the Smartphone. System evaluation involved collecting WMMS output and (separate) camcorder video under realistic conditions for five able-bodied subjects. The subjects each performed a consecutive series of mobility tasks; including, walking, sitting, lying, stairs, ramps, elevator, bathroom activities, kitchen activities, dining activities and outdoor walking. Activity, timing and contextual information were obtained from the camcorder for comparison. Sensitivity results for sensor-based CoS identification were 97-100% for standing, sitting, lying and taking an elevator; 67-73% for walking-related CoS (stairs, ramps); 40-93% between walking and small movements (brushing teeth, etc.); and below 27% for daily living activities. False positives occurred in less than 12% of all activities, with less than 5% false positives for half the measures. Better classification results were achieved when using both acceleration features and Smartphone integrated video for all activities except sitting. The evaluation demonstrated that the WMMS algorithm and BlackBerry platform were effective for detecting mobility activities, even with low sampling rate sensors. The combined sensor and video analysis enhanced mobility task identification and contextual information.