bluuebunny/crossref_metadata_2025 huggingface dataset:
Inverse‐Woodpile Photonic Band Gap Crystals with a Cubic Diamond‐like Structure Made from Single‐Crystalline Silicon
Authors: van den Broek J. M. , Woldering L. A. , Tjerkstra R. W. , Segerink F. B. , Setija I. D. , Vos W. L.
Published: September 2011

Three dimensional photonic band gap crystals with a cubic diamond‐like symmetry are fabricated. These so‐called inverse‐woodpile nanostructures consist of two perpendicular sets of pores in single‐crystal silicon wafers and are made by means of complementary metal oxide–semiconductor (CMOS)‐compatible methods. Both sets of pores have high aspect ratios and are made by deep reactive‐ion etching. The mask for the first set of pores is defined in chromium by means of deep UV scan‐and‐step technology. The mask for the second set of pores is patterned using an ion beam and carefully placed at an angle of 90° with an alignment precision of better than 30 nm. Crystals are made with pore radii between 135–186 nm with lattice parameters a = 686 and c = 488 nm such that a/c = √2; hence the structure is cubic. The crystals are characterized using scanning electron microscopy and X‐ray diffraction. By milling away slices of crystal, the pores are analyzed in detail in both directions regarding depth, radius, tapering, shape, and alignment. Using optical reflectivity it is demonstrated that the crystals have broad reflectivity peaks in the near‐infrared frequency range, which includes the telecommunication range. The strong reflectivity confirms the high quality of the photonic crystals. Furthermore the width of the reflectivity peaks agrees well with gaps in calculated photonic band structures.
Structural and Electronic Properties of Semiconductor‐Sensitized Solar‐Cell Interfaces
Authors: Patrick Christopher E. , Giustino Feliciano
Published: September 2011

A recent study has reported a power‐conversion efficiency of 5.1% for solar cells employing mesoporous TiO2 films sensitized with quantum dots of stibnite (Sb2S3). Here, a first‐principles atomic‐scale investigation of the interface between TiO2 and Sb2S3 is presented. The proposed atomistic interface model is free of defects, and the calculated energy‐level alignment at the interface indicates that the ideal open‐circuit voltage is as high as 1.6 V. Films sensitized with the isostructural compounds bismuthinite (Bi2S3) and antimonselite (Sb2Se3), which exhibit band gaps closer to the ideal Shockley–Queisser value are also examined. In the case of Bi2S3 the calculations indicate that the lowest unoccupied molecular orbital is too low in energy to inject electrons into TiO2, in agreement with experimental data. For antimonselite (Sb2Se3) the calculations predict a type‐II heterojunction with TiO2, and suggest that Sb2Se3 sensitization may lead to higher power conversion efficiencies than found in the TiO2/Sb2S3 system.
Alu polymorphisms in the Waorani tribe from the Ecuadorian Amazon reflect the effects of isolation and genetic drift
Authors: Gómez‐Pérez Luis , Alfonso‐Sánchez Miguel A. , Sánchez Dora , García‐Obregón Susana , Espinosa Ibone , Martínez‐Jarreta Begoña , De Pancorbo Marian M. , Peña José A.
Published: September 2011

Objectives:

The Amazon basin is inhabited by some of the most isolated human groups worldwide. Among them, the Waorani tribe is one of the most interesting Native American populations from the anthropological perspective. This study reports a genetic characterization of the Waorani based on autosomal genetic loci.

Methods:

We analyzed 12 polymorphic Alu insertions in 36 Waorani individuals from different communal longhouses settled in the Yasuní National Park.

Results:

The most notable finding was the strikingly reduced genetic diversity detected in the Waorani, corroborated by the existence of four monomorphic loci (ACE, APO, FXIIIB, and HS4.65), and of other four Alu markers that were very close to the fixation for the presence (PV92 and D1) or the absence (A25 and HS4.32) of the insertion. Furthermore, results of the centroid analysis supported the notion of the Waorani being one of the Amerindian groups less impacted by gene flow processes.

Conclusions:

The prolonged isolation of the Waorani community, in conjunction with a historically low effective population size and high inbreeding levels, have resulted in the drastic reduction of their genetic diversity, because of the effects of severe genetic drift. Recurrent population bottlenecks most likely determined by certain deep‐rooted sociocultural practices of the Waorani (characterized by violence, internal quarrels, and revenge killings until recent times) are likely responsible for this pattern of diversity. The findings of this study illustrate how sociocultural factors can shape the gene pool of human populations. Am. J. Hum. Biol., 2011. © 2011 Wiley‐Liss, Inc.
The stability of immunoglobulin a in human milk and saliva stored on filter paper at ambient temperature
Authors: Miller Elizabeth M. , Mcconnell Daniel S.
Published: September 2011

Objectives:

Immunoglobulin A dominates mucosal surfaces and is a biomarker of interest in populations with a high disease burden. The objectives of this work are to describe an ELISA for IgA and test the stability of storage on filter paper for human milk and saliva collection to be used in remote field locations.

Methods:

A two‐site sandwich ELISA for IgA was developed. To test filter paper storage capabilities under field conditions, 248 matched whole and dried human milk filter paper samples and 251 matched whole and dried saliva samples were collected from northern Kenyan women. Whole samples were frozen in liquid nitrogen while dried samples were stored at ambient temperature for up to 8 weeks. Recovered dried IgA levels were compared to whole IgA levels and adjusted for time stored at ambient temperature.

Results:

The lower limit of quantification for this assay is 10.1 ng/ml. Linearity of dilution for human milk and saliva samples was excellent. High and low‐control coefficient of variation values across plates were 9.1 (341.8 ng/ml) and 9.4% (132.5 ng/ml). IgA was detected in all whole and dried samples. There is a moderate concordance between dried and whole samples (R2 = 0.62). There is a small but significant effect of time stored, with a loss of ∼1 μg/ml per day (P = 0.0052).

Conclusions:

This IgA assay is a cost‐effective alternative to commercial secretory IgA kits. Human milk and saliva can be stored on filter paper for up to 8 weeks. Am. J. Hum. Biol., 2011. © 2011 Wiley‐Liss, Inc.
Collective arousal when reuniting after temporary separation in Tonkean macaques
Authors: De Marco Arianna , Cozzolino Roberto , Dessì‐Fulgheri Francesco , Thierry Bernard
Published: September 2011

Celebrations and bursts of communal joy can occur spontaneously in human communities based on mechanisms of emotional contagion. Some examples of similar collective excitement have been reported in animals when they reunite or anticipate rewards, but little is known about the processes and meaning of these multiple interactions. We experimentally studied such collective arousals in two captive groups of Tonkean macaques (Macaca tonkeana) within the context of reunions following the temporary separation of two subgroups. We compared the behaviors of individuals after separation periods of 2 and 48 h with a control period with no separation. This study showed that it is possible to reproducibly induce bursts of friendly interactions in which groupmates run around over a period of several minutes, embracing and grasping one another while displaying numerous affiliative vocalizations and facial expressions. The longer the period of separation, the higher and longer‐lasting the rates of affiliative interactions were. Individuals affiliated more frequently with groupmates from a previously separated subgroup than with those having stayed in their own subgroup. Collective arousal was followed by a quieter period characterized by high rates of contact‐sitting and social grooming. These results point at the role of collective arousals in social cohesion; they could resolve social tension and renew social relationships. We propose that the emotional state experienced by Tonkean macaques during such events represents a disposition similar to that giving rise to what we humans call “shared joy.” Am J Phys Anthropol, 2011. © 2011 Wiley‐Liss, Inc.
Brief communication: Comparing loading scenarios in lower first molar supporting bone structure using 3D finite element analysis
Authors: Benazzi Stefano , Kullmer Ottmar , Grosse Ian R. , Weber Gerhard W.
Published: September 2011

Finite element analysis (FEA) is a widespread technique to evaluate the stress/strain distributions in teeth or dental supporting tissues. However, in most studies occlusal forces are usually simplified using a single vector (i.e., point load) either parallel to the long tooth axis or oblique to this axis. In this pilot study we show how lower first molar occlusal information can be used to investigate the stress distribution with 3D FEA in the supporting bone structure. The LM1 and the LP2‐LM1 of a dried modern human skull were scanned by μCT in maximum intercuspation contact. A kinematic analysis of the surface contacts between LM1 and LP2‐LM1 during the power stroke was carried out in the occlusal fingerprint analyzer (OFA) software to visualize contact areas during maximum intercuspation contact. This information was used for setting the occlusal molar loading to evaluate the stress distribution in the supporting bone structure using FEA. The output was compared to that obtained when a point force parallel to the long axis of the tooth was loaded in the occlusal basin. For the point load case, our results indicate that the buccal and lingual cortical plates do not experience notable stresses. However, when the occlusal contact areas are considered, the disto‐lingual superior third of the mandible experiences high tensile stresses, while the medio‐lingual cortical bone is subjected to high compressive stresses. Developing a more realistic loading scenario leads to better models to understand the relationship between masticatory function and mandibular shape and structures. Am J Phys Anthropol, 2012. © 2011 Wiley Periodicals, Inc.
Population genetic structure of Guizhou snub‐nosed monkeys (Rhinopithecus brelichi) as inferred from mitochondrial control region sequences, and comparison with R. roxellana and R. bieti
Authors: Yang Mouyu , Yang Yeqin , Cui Duoying , Fickenscher Gisela , Zinner Dietmar , Roos Christian , Brameier Markus
Published: September 2011

The Guizhou snub‐nosed monkey (Rhinopithecus brelichi) is a primate species endemic to the Wuling Mountains in southern China. With a maximum of 800 wild animals, the species is endangered and one of the rarest Chinese primates. To assess the genetic diversity within R. brelichi and to analyze its genetic population structure, we collected fecal samples from the wild R. brelichi population and sequenced the hypervariable region I of the mitochondrial control region from 141 individuals. We compared our data with those from the two other Chinese snub‐nosed species (R. roxellana, R. bieti) and reconstructed their phylogenetic relationships and divergence times. With only five haplotypes and a maximum of 25 polymorphic sites, R. brelichi shows the lowest genetic diversity in terms of haplotype diversity (h), nucleotide diversity (π), and average number of pairwise nucleotide differences (Π). The most recent common ancestor of R. brelichi lived ∼0.36 million years ago (Ma), thus more recently than those of R. roxellana (∼0.91 Ma) and R. bieti (∼1.33 Ma). Phylogenetic analysis and analysis of molecular variance revealed a clear and significant differentiation among the three Chinese snub‐nosed monkey species. Population genetic analyses (Tajima's D, Fu's Fs, and mismatch distribution) suggest a stable population size for R. brelichi. For the other two species, results point in the same direction, but population substructure possibly introduces some ambiguity. Because of the lower genetic variation, the smaller population size and the more restricted distribution, R. brelichi might be more vulnerable to environmental changes or climate oscillations than the other two Chinese snub‐nosed monkey species. Am J Phys Anthropol, 2012. © 2011 Wiley Periodicals, Inc.
Regio‐ und chemoselektive Metallierung von Arenen und Heteroarenen mit gehinderten Metallamidbasen
Authors: Haag Benjamin , Mosrin Marc , Ila Hiriyakkanavar , Malakhov Vladimir , Knochel Paul
Published: September 2011

Die Synthese hoch funktionalisierter Organometallverbindungen gelingt durch C‐H‐Aktivierung zahlreicher ungesättigter Substrate mit Lithiumchlorid‐solubilisierten 2,2,6,6‐Tetramethylpiperidyl‐Basen (TMPnMXm⋅p LiCl). Diese Reagentien erweisen sich als exzellent zur Umwandlung vielfältiger aromatischer sowie heterocyclischer Substrate in nützliche metallorganische Reagentien mit weiter Anwendungsbreite in der organischen Synthese.
Kinetics of thermal degradation of polysulfone/polyimide blended polymeric membranes
Authors: Rafiq Sikander , Man Zakaria , Maitra Saikat , Muhammad Nawshad , Ahmad Farooq
Published: September 2011

Flat‐sheet asymmetric polysulfone (PSF)/polyimide (PI) blended membranes were fabricated by a phase‐inversion technique. The fabricated membranes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and field emission scanning electron microscopy analyses. The kinetics of thermal degradation of the membranes were studied from thermogravimetric data following Friedman's kinetic approach. The thermal degradation process of the membranes followed first‐order rate kinetics, and the activation energy of the thermal degradation process increased with increasing PI content of the membrane compositions. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Freeze–thaw resistance of unidirectional‐fiber‐reinforced epoxy composites
Authors: Li Hui , Xian Guijun , Lin Qi , Zhang Hui
Published: September 2011

The freeze–thaw resistance of unidirectional glass‐, carbon‐, and basalt‐fiber‐reinforced polymer (GFRPs, CFRPs, and BFRPs, respectively) epoxy wet layups was investigated from −30 to 30°C in dry air. Embedded optic‐fiber Bragg grating sensors were applied to monitor the variation of the internal strain during the freeze–thaw cycles, with which the coefficient of thermal expansion (CTE) was estimated. With the CTE values, the stresses developed in the matrix of the FRPs were calculated, and CFRPs were slightly higher than in the BFRP and GFRP cases. The freeze–thaw cycle showed a negligible effect on the tensile properties of both GFRP and BFRP but exhibited an adverse effect on CFRP, causing a reduction of 16% in the strength and 18% in the modulus after 90 freeze–thaw cycles. The susceptibility of the bonding between the carbon fibers and epoxy to the freeze–thaw cycles was assigned to the deterioration of CFRP. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Effects of compaction and UV exposure on performance of acrylate/glass‐fiber composites cured layer by layer
Authors: Duan Yugang , Li Jia , Zhong Weihong , Maguire Russell G. , Zhao Guoqiang , Xie Hong , Li Dichen , Lu Bingheng
Published: September 2011

With an aim to reducing manufacturing costs, in general and specifically to provide a solution to the thick laminate curing depth issue for composite materials, UV curing technology was combined with a fiber placement process to fabricate acrylate/glass‐fiber composites. A novel layer‐by‐layer UV in situ curing method was employed in this article and interlaminar shear strength (ILSS) tests and SEM were used to evaluate the effect of processing parameters, including compaction force and UV exposure dose, on ILSS. The SEM images from short‐beam strength test samples and the results of ILSS showed that the fibers' distribution was uniform in the cured matrix resin resulting from the compaction forces and that beneficially influenced the ILSS of the composite greatly. However, the matrix resin produced large shrinkage stresses when it reached a high degree of conversion (DC) in one‐step, which resulted in poor interlaminar adhesion. In addition, the fast curing speed of UV on the composite resulted in poor wetting between fiber and resin, and accordingly resulted in lower ILSS. To overcome these problems and obtain high ILSS value composites, an optimized compaction force and UV exposure dose were determined experimentally. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Ontogenetic Allometry and Cranial Shape Diversification Among Human Populations From South America
Authors: Gonzalez Paula N. , Perez S. Ivan , Bernal Valeria
Published: September 2011

Modifications of ontogenetic allometries play an important role in patterning the shape differentiation among populations. This study evaluates the influence of size variation on craniofacial shape disparity among human populations from South America and assesses whether the morphological disparity observed at the interpopulation level resulted from a variable extension of the same ontogenetic allometry, or whether it arose as a result of divergences in the pattern of size‐related shape changes. The size and shape of 282 adult and subadult crania were described by geometric morphometric‐based techniques. Multivariate regressions were used to evaluate the influence of size on shape differentiation between and within populations, and phylogenetic comparative methods were used to take into account the shared evolutionary history among populations. The phylogenetic generalized least‐squares models showed that size accounts for a significant amount of shape variation among populations for the vault and face but not for the base, suggesting that the three modules did not exhibit a uniform response to changes in overall growth. The common slope test indicated that patterns of evolutionary and ontogenetic allometry for the vault and face were similar and characterized by a heightening of the face and a lengthening of the vault with increasing size. The conservation of the same pattern of shape changes with size suggests that differences in the extent of growth contributed to the interpopulation cranial shape variation and that certain directions of morphological change were favored by the trait covariation along ontogeny. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.
DNA Methylation and Nonsmall Cell Lung Cancer
Authors: Lu Fang , Zhang Hong‐Tao
Published: September 2011

Lung cancer is the leading cause of cancer‐related death in men and women worldwide. Owing to the scarcity of effective tools for early detection and therapy strategies, the 5‐year survival rate of lung cancer is very poor. Because the accumulation of multiple genetic and/or epigenetic changes, including DNA methylation, has been suggested to contribute to development and progression of human cancers, improved understanding of the relationship between DNA methylation and lung cancer will provide new insights for identifying promising biomarkers for diagnosis, prognosis, and treatment of lung cancer. Here, we present a relatively comprehensive review of DNA methylation and lung cancer, discuss DNA methylation changes in carcinogenesis and metastasis of lung cancer, and explore the association of microRNA with DNA methylation. Additionally, we outline the applications of DNA methylation in clinical practice, such as diagnosis, prognosis, and therapy of lung cancer. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.
Changes in Triacylglycerol‐Accumulated Fiber Type, Fiber Type Composition, and Biogenesis in the Mitochondria of the Soleus Muscle in Obese Rats
Authors: Kaneko Syuhei , Iida Ryo‐Hei , Suga Takeo , Fukui Tadayoshi , Morito Mitsuhiko , Yamane Akira
Published: September 2011

Little is known about the effects of obesity on skeletal muscle consisting of approximately 80% type I (slow) fibers, such as that in the soleus muscle, although type I fibers have an enhanced capacity for mitochondrial respiration and fatty acid oxidation. We investigated the effects of obesity on the soleus muscle in the rat. Rats were fed a high‐fat diet (protein:fat:carbohydrate = 20:57:23; 508 kcal/100 g) or a control diet (protein:fat:carbohydrate = 20:10:70; 366 kcal/100 g) for 10 weeks. We analyzed the accumulation of intramyocellular triacylglycerol (IMTG), fiber type composition, and the biogenesis and function of the mitochondria in the soleus muscle of the rat during 10 weeks of feeding, using histochemical and real‐time polymerase chain reaction analyses. Obesity increased body weight and markedly elevated IMTG levels in type I, but not in type II, fibers of the soleus muscle throughout the feeding period. Obesity also inhibited the biogenesis and function in the mitochondria and altered the fiber type composition in the soleus muscle. The suppression of biogenesis and function in the mitochondria, and the alteration in the fiber type composition may be attributable to the marked IMTG accumulation in the soleus muscle of the rat. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.
mSmile is Necessary for Bronchial Smooth Muscle and Alveolar Myofibroblast Development
Authors: Yun Eun Jun , Vu Thiennu H.
Published: September 2011

Disrupted lung alveolar myofibroblast and bronchial smooth muscle (BSM) cell development may lead to pulmonary disorders such as bronchopulmonary dysplasia. The molecular mechanisms that regulate BSM and alveolar myofibroblast development are not fully understood. Here we show that mSmile (murine Smile), a novel transmembrane protein with tetratricopeptide repeats, functions in lung alveolar myofibroblast and BSM cell development. mSmile mutant mice exhibit early neonatal lethality with few mice surviving up to 3 weeks. Mutant lungs display both airway branching morphogenesis defect during fetal lung development and alveolarization defect after birth. These defects are associated with reduced numbers of BSM cells in the peribronchial subepithelial region and clefts and myofibroblasts in alveolar septae. Expression of fibroblast growth factor‐10 and its down stream target Bmp‐4, which are important for BSM formation, is decreased. In vitro, mSmile mutant embryonic fibroblasts show reduced receptor activation and induction of myofibroblast formation in response to Transforming growth factor‐β (Tgf‐β), indicating that mSmile may mediate myofibroblast development through modulation of Tgf‐β signaling. These studies identify mSmile as a novel gene specifying both the BSM and lung alveolar myofibroblast lineages, contributing to our understanding of the biological control of the development of these cells, and may provide insights into the aberrant smooth muscle and alveolar myofibroblast development that occur in pathological conditions. Anat Rec, 2012. © 2011 Wiley Periodicals, Inc.
Design, Synthesis, and Antiproliferative Activity of 3,4‐Diarylpyrazole‐1‐carboxamide Derivatives Against Melanoma Cell Line
Authors: El‐Gamal Mohammed I. , Choi Hong Seok , Cho Hae‐Guk , Hong Jun Hee , Yoo Kyung Ho , Oh Chang‐Hyun
Published: September 2011

Synthesis of a new series of 3,4‐diarylpyrazole‐1‐carboxamide derivatives is described. Their antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The biological results indicated that five synthesized compounds (Ig, Ii, IIc, IIg, and IIh) exhibited similar activity to Sorafenib. In addition, three compounds (IIa, IIb, and IIi) were more potent than Sorafenib. Among all of these derivatives, compound IIa which has dimethylamino and phenolic moieties showed the most potent antiproliferative activity against A375P human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIa into the domain of V600E‐b‐Raf and the binding mode was studied.
CXCL12γ isoform is expressed on endothelial and dendritic cells in rheumatoid arthritis synovium and regulates T cell activation
Authors: Santiago Begoña , Izquierdo Elena , Rueda Patricia , Rey Manuel J. Del , Criado Gabriel , Usategui Alicia , Arenzana‐Seisdedos Fernando , Pablos José L.
Published: September 2011

Objective

CXCL12γ is an alternative splicing isoform of CXCL12 with enhanced affinity for heparan sulfate (HS) proteoglycans. This study was undertaken to investigate the distribution and potential function of CXCL12γ in rheumatoid arthritis (RA) synovium and normal lymphoid tissue, where its immobilization to HS may be relevant in pathologic or homeostatic immune cell migration and activation.

Methods

Expression of CXCL12 or CXCL12γ was immunodetected in RA and normal synovium, lymphoid tissue, and cultured cells with anti–pan‐CXCL12 or anti‐CXCL12γ–specific monoclonal antibodies. CXCL12α and CXCL12γ messenger RNA expression was analyzed by quantitative reverse transcription–polymerase chain reaction. Binding of wild‐type CXCL12 isoforms or their HS binding–defective mutants to monocyte‐derived dendritic cells (DCs) was analyzed by flow cytometry. The effect of DC‐bound CXCL12α and CXCL12γ on T cell activation was analyzed in DC/T cell allogeneic cultures.

Results

CXCL12γ expression was increased in RA compared to normal synovium and preferentially located in endothelia and DC‐SIGN–positive cells. This distribution was also observed in lymphoid organs. Surface‐bound CXCL12γ was detected in a fraction of freshly isolated DCs. Monocyte‐derived DCs, but not monocytes, showed a high capacity to bind CXCL12γ in an HS‐dependent manner. Surface‐bound CXCL12α and CXCL12γ on monocyte‐derived DCs were potent inhibitors of allogeneic T cell activation, in contrast to the T cell–stimulatory effects of soluble CXCL12 proteins.

Conclusion

CXCL12γ shows a specific and similar distribution in RA synovium and lymphoid tissue, consistent with its higher HS binding affinity. Presentation of CXCL12 to T cells on membrane HS in DCs can play a distinct regulatory role in T cell activation.
Interferon signals and monocytic sensitization of the interferon‐γ signaling pathway in the peripheral blood of patients with rheumatoid arthritis
Authors: Karonitsch Thomas , von Dalwigk Karolina , Steiner Carl W. , Blüml Stephan , Steiner Günter , Kiener Hans P. , Smolen Josef S. , Aringer Martin
Published: September 2011

Objective

Both type I interferons (IFNα and IFNβ) and type II IFN (IFNγ) signal via pSTAT‐1. Immunohistochemistry and the gene expression signatures of rheumatoid arthritis (RA) synovial tissue suggest an activated IFN/STAT‐1 signaling pathway. The aim of this study was to determine the systemic activity of the IFN/STAT‐1 signaling pathway in the peripheral blood cells of patients with RA.

Methods

Fluorocytometry or quantitative polymerase chain reaction was used to measure the expression of STAT‐1, pSTAT‐1, and IFN‐inducible genes (monokine induced by interferon‐γ [MIG], interferon‐γ–inducible protein 10 [IP‐10], and 2′,5′‐oligoadenylate synthetase [OAS]) in the peripheral blood mononuclear cells (PBMCs) and purified CD14+ peripheral blood monocytes of patients with RA and healthy control subjects. PBMCs were also incubated for 48 hours with IFNs and several other cytokines to investigate influences on STAT‐1 levels. To examine the significance of STAT‐1 activation in RA monocytes after stimulation with IFNγ, the expression of pSTAT‐1 and of the IFNγ‐inducible chemokine MIG was measured using fluorocytometry.

Results

Levels of STAT‐1 were significantly increased in peripheral lymphocytes and monocytes from patients with RA compared with those from healthy control subjects. STAT‐1 levels correlated well with RA disease activity, as measured by the Disease Activity Score in 28 joints and the Clinical Disease Activity Index. Furthermore, STAT‐1 messenger RNA expression in RA CD14+ monocytes correlated with the expression of other IFN‐target genes, such as IP‐10, OAS, or MIG. In RA PBMCs, STAT‐1 expression was increased not only by IFNs but also by tumor necrosis factor. RA monocytes demonstrated a considerably higher increase in pSTAT‐1 and MIG levels upon IFNγ stimulation when compared with monocytes from control subjects, indicating that RA monocytes are more sensitive to IFNγ stimulation.

Conclusion

In addition to supporting the role of IFNs in systemic proinflammatory activity, the results of this study further suggest preactivation of the IFNγ/STAT‐1 signaling pathway, especially in RA monocytes.
Evidence for gene–gene epistatic interactions among susceptibility loci for systemic lupus erythematosus
Authors: Hughes Travis , Adler Adam , Kelly Jennifer A. , Kaufman Kenneth M. , Williams Adrienne H. , Langefeld Carl D. , Brown Elizabeth E. , Alarcón Graciela S. , Kimberly Robert P. , Edberg Jeffrey C. , Ramsey‐Goldman Rosalind , Petri Michelle , Boackle Susan A. , Stevens Anne M. , Reveille John D. , Sanchez Elena , Martín Javier , Niewold Timothy B. , Vilá Luis M. , Scofield R. Hal , Gilkeson Gary S. , Gaffney Patrick M. , Criswell Lindsey A. , Moser Kathy L. , Merrill Joan T. , Jacob Chaim O. , Tsao Betty P. , James Judith A. , Vyse Timothy J. , Alarcón‐Riquelme Marta E. ,   BIOLUPUS Network, Harley John B. , Richardson Bruce C. , Sawalha Amr H.
Published: September 2011

Objective

Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene–gene interactions in a number of known lupus susceptibility loci.

Methods

Eighteen single‐nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2‐step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing.

Results

We detected and confirmed gene–gene interactions between the HLA region and CTLA4, IRF5, and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 × 10−5 [FDR ≤0.05], P for multifactor dimensionality reduction = 5.9 × 10−45). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P = 0.0028 and P = 0.0047, respectively).

Conclusion

We provide evidence for gene–gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
NLRP3 inflammasome–mediated neutrophil recruitment and hypernociception depend on leukotriene B4 in a murine model of gout
Authors: Amaral Flávio A. , Costa Vivian V. , Tavares Livia D. , Sachs Daniela , Coelho Fernanda M. , Fagundes Caio T. , Soriani Frederico M. , Silveira Tatiana N. , Cunha Larissa D. , Zamboni Dario S. , Quesniaux Valerie , Peres Raphael S. , Cunha Thiago M. , Cunha Fernando Q. , Ryffel Bernhard , Souza Daniele G. , Teixeira Mauro M.
Published: September 2011

Objective

Deposition of monosodium urate monohydrate (MSU) crystals in the joints promotes an intense inflammatory response and joint dysfunction. This study evaluated the role of the NLRP3 inflammasome and 5‐lipoxygenase (5‐LOX)–derived leukotriene B4 (LTB4) in driving tissue inflammation and hypernociception in a murine model of gout.

Methods

Gout was induced by injecting MSU crystals into the joints of mice. Wild‐type mice and mice deficient in NLRP3, ASC, caspase 1, interleukin‐1β (IL‐1β), IL‐1 receptor type I (IL‐1RI), IL‐18R, myeloid differentiation factor 88 (MyD88), or 5‐LOX were used. Evaluations were performed to assess neutrophil influx, LTB4 activity, cytokine (IL‐1β, CXCL1) production (by enzyme‐linked immunosorbent assay), synovial microvasculature cell adhesion (by intravital microscopy), and hypernociception. Cleaved caspase 1 and production of reactive oxygen species (ROS) were analyzed in macrophages by Western blotting and fluorometric assay, respectively.

Results

Injection of MSU crystals into the knee joints of mice induced neutrophil influx and neutrophil‐dependent hypernociception. MSU crystal–induced neutrophil influx was CXCR2‐dependent and relied on the induction of CXCL1 in an NLRP3/ASC/caspase 1/IL‐1β/MyD88–dependent manner. LTB4 was produced rapidly after injection of MSU crystals, and this was necessary for caspase 1–dependent IL‐1β production and consequent release of CXCR2‐acting chemokines in vivo. In vitro, macrophages produced LTB4 after MSU crystal injection, and LTB4 was relevant in the MSU crystal–induced maturation of IL‐1β. Mechanistically, LTB4 drove MSU crystal–induced production of ROS and ROS‐dependent activation of the NLRP3 inflammasome.

Conclusion

These results reveal the role of the NLRP3 inflammasome in mediating MSU crystal–induced inflammation and dysfunction of the joints, and highlight a previously unrecognized role of LTB4 in driving NLRP3 inflammasome activation in response to MSU crystals, both in vitro and in vivo.
Risk factors for relapse of antineutrophil cytoplasmic antibody–associated vasculitis
Authors: Walsh Michael , Flossmann Oliver , Berden Annelies , Westman Kerstin , Höglund Peter , Stegeman Coen , Jayne David ,   European Vasculitis Study Group
Published: September 2011

Objective

To determine the association between characteristics at diagnosis and the time to first relapse in a large cohort of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV).

Methods

We studied long‐term followup data from 4 clinical trials that included newly diagnosed patients with a broad spectrum of AAV severity and manifestations. Patient and disease characteristics at baseline were used in competing risk regression models with relapse as the event of interest and death as the competing event.

Results

We assessed 535 patients with 1,804 patient‐years at risk of relapse. At diagnosis, the median age was 60.7 years (interquartile range [IQR] 48.8–69.1 years), 284 patients (53%) had granulomatosis with polyangiitis (Wegener's), and the median creatinine level was 203 μmoles/liter (IQR 97–498). A total of 201 patients (38%) experienced a relapse and 133 patients (25%) died, 96 of whom had not had prior relapse. Anti–proteinase 3 antibodies (subhazard ratio [sHR] 1.62 [95% confidence interval 1.39–1.89]) and cardiovascular involvement (sHR 1.59 [95% confidence interval 1.07–2.37]) were independently associated with a higher risk of relapse. Compared with patients with a creatinine level ≤100 μmoles/liter, patients with higher creatinine levels had a lower risk of relapse (sHR 0.81 [95% confidence interval 0.77–0.85] for a creatinine level of 101–200 μmoles/liter; sHR 0.39 [95% confidence interval 0.22–0.69] for a creatinine level >200 μmoles/liter).

Conclusion

Relapse of disease is common for patients with AAV. A creatinine level >200 μmoles/liter at the time of diagnosis is strongly associated with a reduced risk of relapse and may help guide monitoring and treatment of patients with AAV.
Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity
Authors: Liu Yin , Ramot Yuval , Torrelo Antonio , Paller Amy S. , Si Nuo , Babay Sofia , Kim Peter W. , Sheikh Afzal , Lee Chyi‐Chia Richard , Chen Yongqing , Vera Angel , Zhang Xue , Goldbach‐Mansky Raphaela , Zlotogorski Abraham
Published: September 2011

Objective

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome) is an autoinflammatory syndrome recently described in children. We undertook this study to investigate the clinical phenotype, genetic cause, and immune dysregulation in 9 CANDLE syndrome patients.

Methods

Genomic DNA from all patients was screened for mutations in PSMB8 (proteasome subunit β type 8). Cytokine levels were measured in sera from 3 patients. Skin biopsy samples were evaluated by immunohistochemistry, and blood microarray profile and STAT‐1 phosphorylation were assessed in 4 patients and 3 patients, respectively.

Results

One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A), suggesting a protein truncation; 4 patients were homozygous and 2 were heterozygous for a previously reported missense mutation (c.224C>T); and 1 patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the 4 patients with the same mutation, only 2 shared the same haplotype, indicating a mutational hot spot. PSMB8 mutation–positive and –negative patients expressed high levels of interferon‐γ (IFNγ)–inducible protein 10. Levels of monocyte chemotactic protein 1, interleukin‐6 (IL‐6), and IL‐1 receptor antagonist were moderately elevated. Microarray profiles and monocyte STAT‐1 activation suggested a unique IFN signaling signature, unlike in other autoinflammatory disorders.

Conclusion

CANDLE syndrome is caused by mutations in PSMB8, a gene recently reported to cause “JMP” syndrome (joint contractures, muscle atrophy, microcytic anemia, and panniculitis‐induced childhood‐onset lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8‐associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target.
CREMα suppresses spleen tyrosine kinase expression in normal but not systemic lupus erythematosus T cells
Authors: Ghosh Debjani , Kis‐Toth Katalin , Juang Yuang‐Taung , Tsokos George C.
Published: September 2011

Objective

T cells from patients with systemic lupus erythematosus (SLE) display increased amounts of spleen tyrosine kinase (Syk), which is involved in the aberrant CD3/T cell receptor–mediated signaling process, and increased amounts of CREMα, which suppresses the production of interleukin‐2. Syk expression can be suppressed by CREMα. This study was undertaken to investigate why CREMα fails to suppress Syk expression in SLE T cells.

Methods

CREMα was overexpressed in healthy T cells by transfection with CREMα expression vector, and Syk expression and phosphorylation were measured. A newly identified cAMP response element (CRE) site on theSYKpromoter was characterized by chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay. The CREMα‐mediated repression of Syk expression was further evaluated by analyzingSYKpromoter activity. T cells from SLE patients and healthy individuals were subjected to ChIP to evaluate CREMα binding and histone H3 acetylation.

Results

Increased CREMα levels suppressed Syk expression by direct binding to a CRE site of theSYKpromoter in T cells from healthy individuals but failed to do so in T cells from SLE patients. The failure of CREMα to suppress Syk expression in SLE T cells was due to weaker binding to the CRE site of theSYKpromoter compared to healthy T cells because the promoter site is hypoacetylated in SLE T cells and therefore of limited access to transcription factors.

Conclusion

Our findings indicate that epigenetic alteration of theSYKpromoter in SLE T cells results in the inability of the transcriptional repressor CREMα to bind and suppress the expression of Syk, resulting in aberrant T cell signaling.
The autoantigen DNA topoisomerase I interacts with chemokine receptor 7 and exerts cytokine‐like effects on dermal fibroblasts
Authors: Arcand Julie , Robitaille Geneviève , Koenig Martial , Senécal Jean‐Luc , Raymond Yves
Published: September 2011

Objective

Previous studies have demonstrated that, once released into the extracellular environment, the systemic sclerosis (SSc)–associated autoantigen DNA topoisomerase I (topo I) binds specifically to the surface of fibroblasts via an unknown receptor. We extended these results by identifying topo I–mediated cellular effects and characterizing the specific target of topo I on fibroblast surfaces.

Methods

Purified topo I was used to investigate intracellular signaling pathway activation and tested for cell migration. To demonstrate the expression of specific chemokine receptors on fibroblasts, we performed immunoblotting and flow cytometry. To evaluate the direct interaction between chemokine receptor and topo I, a protein–protein based enzyme‐linked immunosorbent assay (ELISA) was used. Finally, topo I coupled to the fluorochrome phycoerythrin (PE) was used to investigate competition of topo I specific binding on fibroblast surfaces with chemokine ligand.

Results

Topo I stimulated the phosphorylation of phospholipase Cγ1, c‐Raf, ERK‐1/2, and p38 MAPK, intracellular signaling pathways that stimulated fibroblast migration via a Gαi protein–coupled receptor. CCR7 was found to interact directly with topo I. Furthermore, its ligand, CCL21, competed in vitro for this interaction and in vivo with the binding of PE‐coupled topo I to fibroblast surfaces.

Conclusion

These new roles of topo I in fibroblast physiology and the identification of its target on the cell surface demonstrate that topo I is a bifunctional autoantigen and open up new perspectives of study in the field of SSc‐associated anti–topo I autoantibodies.
Metabolic effects of high‐dose prednisolone treatment in early rheumatoid arthritis: Balance between diabetogenic effects and inflammation reduction
Authors: den Uyl Debby , van Raalte Daniel H. , Nurmohamed Michael T. , Lems Willem F. , Bijlsma Johannes W. J. , Hoes Jos N. , Dijkmans Ben A. C. , Diamant Michaela
Published: September 2011

Objective

To investigate the dose‐related effects of glucocorticoid treatment on glucose tolerance, beta cell function, and insulin sensitivity in patients with early active rheumatoid arthritis (RA).

Methods

A randomized, controlled, single‐blind trial was conducted in 41 patients with early active RA. At the beginning of the trial patients had not been treated for their RA, and were randomized to begin treatment with prednisolone at 60 mg/day or 30 mg/day. Before and at the end of 1 week of treatment, a frequently sampled oral glucose tolerance test was performed. The glucose area under the curve (AUCG) was calculated. In addition, beta cell function and insulin sensitivity parameters were computed.

Results

Patients (mean ± SD age 55.5 ± 14.8 years and 54.2 ± 12.6 years in the prednisone 60 mg/day and prednisone 30 mg/day groups, respectively; body mass index 24.5 ± 4.1 kg/m2 and 25.4 ± 4.2 kg/m2, respectively) had active disease at baseline (mean ± SD Disease Activity Score in 44 joints 4.1 ± 0.7 and 4.0 ± 0.8, respectively; median C‐reactive protein [CRP] level 14 mg/liter [interquartile range 6–34] and 19 mg/liter [interquartile range 3–39], respectively). In addition, 56% of the patients had impaired glucose tolerance at baseline, and 7% were found to have previously unrecognized type 2 diabetes mellitus (DM). Associations of the AUCG with erythrocyte sedimentation rate (β = 2.430 [95% confidence interval 0.179–4.681], P = 0.04) and with CRP level (β = 2.358 [95% confidence interval 0.210–4.506], P = 0.03) were demonstrated. Treatment with prednisolone at both dosages reduced CRP levels significantly. The incidence of type 2 DM increased to 24% (P < 0.001) (evenly distributed across the groups). The mean AUCG did not change in either treatment arm. Beta cell function improved during prednisone treatment at 60 mg/day (P = 0.02) and at 30 mg/day (P = 0.04). Disease duration was associated with changes in the AUCG (β = 3.626 [95% confidence interval 1.077–6.174], P = 0.007) and with deterioration of the glucose state (odds ratio 1.068 [95% confidence interval 1.017–1.122], P = 0.009).

Conclusion

In this study, short‐term treatment with prednisolone 60 mg or 30 mg per day improved disease activity without deterioration of glucose tolerance in patients with active RA. However, due to individual differences, monitoring is recommended.
Usefulness of anti‐p155 autoantibody for diagnosing cancer‐associated dermatomyositis: A systematic review and meta‐analysis
Authors: Trallero‐Araguás Ernesto , Rodrigo‐Pendás Jose Ángel , Selva‐O'Callaghan Albert , Martínez‐Gómez Xavier , Bosch Xavier , Labrador‐Horrillo Moisés , Grau‐Junyent Josep Maria , Vilardell‐Tarrés Miquel
Published: September 2011

Objective

Anti‐p155 autoantibody, which was recently described in adult patients with dermatomyositis (DM), seems to be associated with cancer in this population. We performed a systematic review and meta‐analysis to ascertain the accuracy of anti‐p155 testing for the diagnosis of cancer‐associated myositis.

Methods

We searched relevant databases, with no restrictions on study design or language, for original studies that included adult patients with probable/definite DM or amyopathic DM who were evaluated for neoplasm and anti‐p155 status. Pooled sensitivity and specificity were calculated using a bivariate model. We computed the diagnostic odds ratio (OR), likelihood ratios (LRs) for positive and negative test results, positive and negative predictive values, and the summary receiver operating characteristic (SROC) curve. Statistical heterogeneity between studies was assessed using the I2 statistic, and 95% confidence intervals (95% CIs) were computed for the parameters studied.

Results

Six studies including a total of 312 adult patients with DM were selected. The pooled sensitivity of anti‐p155 for diagnosing cancer‐associated DM was 78% (95% CI 45–94%), and specificity was 89% (95% CI 82–93%). The diagnostic OR was 27.26 (95% CI 6.59–112.82), and LRs for positive and negative test results were 6.79 (95% CI 4.11–11.23) and 0.25 (95% CI 0.08–0.76), respectively. Heterogeneity was substantial except with regard to the LR for a positive test result. The area under the SROC curve was 0.91 (95% CI 0.88–0.93). Taking the pooled prevalence of 17% as pretest probability, anti‐p155 had a positive predictive value of 58% and a negative predictive value of 95%.

Conclusion

Our findings indicate that anti‐p155 autoantibody determination is useful for diagnosing cancer‐associated myositis and guiding disease management.
Presenting numerical values within sentences and text tables
Authors: Kozak Marcin , Hartley James
Published: September 2011

A text table is a simple table, with no or minimal chartlike elements, that is incorporated directly within a sentence. It can be very efficient in conveying quantitative (and sometimes qualitative) information that can be difficult to read within one or two sentences, but which is too simple to present within a regular table. Although this format has been used in the scientific literature, and indeed recommended in some sources, its effectiveness has not been studied in formal surveys. This article presents the results of one such survey in which three examples were considered. Scientists representing mathematics, statistics, and similar disciplines and scientists representing biology, agriculture, and similar disciplines were asked to participate in the survey; 189 representing the former and 201 representing the latter agreed. The results clearly showed for both groups, when the data presented were suitable for such a layout, that the text tables were much preferred to the original sentences. The main conclusion from this work, therefore, is that scientific authors should use text tables whenever appropriate.