bluuebunny/crossref_metadata_2025 huggingface dataset:
Habitat diversity relative to wave action on rocky shores: implications for the selection of marine protected areas
Authors: Blamey Laura K. , Branch George M.
Published: December 2008

Current selection of marine protected areas in South Africa is based on objective criteria including biogeographic representation and habitat heterogeneity. This paper specifically examines rocky shores on the west coast of South Africa to determine whether they are divisible into discrete ‘habitats’ that need independent conservation.

Seventeen rocky shores spanning the full spectrum of wave exposure were compared in terms of maximum wave forces, biomass, species richness and diversity among zones and sites. Three biotic assemblages were identified, characterizing sheltered, semi‐exposed to exposed, and very exposed habitats. Differences among these were clear‐cut low on the shore but disappeared at the top of the shore where wave action was attenuated and desiccation uniformly intense.

The recognition of three discrete biologically‐defined habitats means that rocky shores cannot be regarded as a uniform habitat for conservation purposes. All three components need protection if the full spectrum of rocky‐shore communities is to be conserved.

It is argued that this approach allows habitats to be defined in an objective manner, and that once this has been done, habitat heterogeneity constitutes a better measure of conservation value of an area than a ‘hotspot’ approach based on species richness and endemism.

Copyright © 2008 John Wiley & Sons, Ltd.
Status, ecology and conservation of an endemic fish, Oreochromis niloticus baringoensis, in Lake Baringo, Kenya
Authors: Britton J.R. , Jackson M.C. , Muchiri M. , Tarras‐Wahlberg H. , Harper D.M. , Grey J.
Published: December 2008

The tilapia Oreochromis niloticus baringoensis is a genetically and morphologically distinct sub‐species of Oreochromis niloticus endemic to Lake Baringo, Kenya. In recent years, concern has been expressed as to its status. Recent declines in catch returns suggest the population may be threatened, with conservation action required to safeguard it.

Catch returns from the Baringo fishery since 1964 have shown considerable fluctuations for all species, but especially O. n. baringoensis. From a peak of 712 t in 1970, their total catch was only 5 t in 2005, despite a 2 year period of closure in 2002 and 2003. Changes in fishery catch and relative abundance were independent of exploitation in the fishery but were significantly correlated with lake level.

Few individuals were captured at lengths >250 mm, with no fish sampled >284 mm. During periods of high lake level, individuals matured at smaller sizes and were capable of growing to larger ultimate sizes. With maturity at lengths <130 mm and fishery regulations preventing removal of fish <180 mm, there was a relatively large proportion of mature fish that was below exploitation size each year (19 to 44%). In most years, the proportion of fish available for exploitation was <10%.

Stable isotope analyses revealed O. n. baringoensis was reliant upon planktonic basal resources and zooplankton carbon. There was only minimal trophic overlap with other fish species in the lake, indicating little potential for competition for food resources.

These data suggest that the population status of O. n. baringoensis is not threatened per se, but subject to an unpredictable and unstable environment that strongly influences their life‐history traits and, ultimately, their population abundance, and should be managed accordingly.

Copyright © 2008 John Wiley & Sons, Ltd.
Ablation of Lung Epithelial Cells Deregulates FGF‐10 Expression and Impairs Lung Branching Morphogenesis
Authors: Kim Namjin , Yamamoto Hiroaki , Pauling Michelle Haynes , Lorizio Walter , Vu Thiennu H.
Published: December 2008

Epithelial‐mesenchymal interactions are essential for tissue patterning during organogenesis. Distal lung epithelium and its adjacent mesenchyme comprise the epithelial‐mesenchymal signaling unit that regulates lung branching morphogenesis. Tissue recombination experiments have demonstrated the importance of mesenchymal signals in inducing lung epithelial differentiation and branching, but the role of the epithelium in regulating mesenchymal signals has not been well characterized. Using transgenic mice, we ablated distal lung epithelial cells during lung development by inducing the expression of a constitutively active proapoptotic Bax protein under the surfactant protein C (SP‐C) promoter. We found that epithelial cell ablation results in impaired lung branching morphogenesis, which progresses to emphysematous airspaces in the adults. Mesenchymal expression of fibroblast growth factor 10 (Fgf‐10), whose strict spatial and temporal expression is critical for proper lung branching morphogenesis, is disrupted and loses its localized pattern. Interestingly, the expression of sonic hedgehog (Shh), an epithelial gene known to modulate Fgf‐10 expression, is unchanged, indicating the existence of other distal epithelial signals that regulate mesenchymal Fgf‐10expression. We propose that distal SP‐C expressing lung epithelial cells provide essential signals for the downregulation of Fgf‐10expression in the distal mesenchyme during lung development. 292:123–130, 2009. © 2008 Wiley‐Liss, Inc.
A case–control study to assess sensitivity and specificity of a questionnaire for the detection of hip and knee osteoarthritis
Authors: Morvan J. , Roux C. H. , Fautrel B. , Rat A. C. , Euller‐Ziegler L. , Loeuille D. , Banal F. , Mazieres B. , Coste J. , Saraux A. , Guillemin F.
Published: December 2008

Objective

To assess the performance of a telephone‐administered questionnaire suitable for use in 2‐phase surveys in the detection of symptomatic hip and knee osteoarthritis (OA) cases.

Methods

A questionnaire was designed based on typical symptoms and self‐reported OA diagnosis. Three groups of subjects were consecutively enrolled from rheumatology units at French university hospitals. The disease status, based on American College of Rheumatology criteria, was first confirmed by a rheumatologist. Subjects then completed the screening questionnaire administered by interviewers unaware of the diagnosis and the clinical examination results. Three screening strategies were evaluated.

Results

In all, 119 subjects with hip OA, 137 with knee OA, and 111 subjects with other rheumatic diseases with lower extremity symptoms were recruited. The highest sensitivity for both hip and knee OA was obtained with the strategy based on reporting the presence or absence of symptoms (>96%). The specificity of this strategy was low (42% for both joints). When taking into account the self‐reported OA diagnosis, the sensitivity slightly decreased (>91%), and the specificity increased greatly, from 76% to 78%. The highest specificity was obtained with the third strategy, requiring a rheumatologist opinion (from 82% to 85%) at the expense of lower sensitivity (>90%).

Conclusion

The questionnaire tested in this study is a simple, valid, and reliable instrument to screen symptomatic hip and knee OA. As such, it fails to reach complete accuracy and clinical examination and radiographs remain necessary for complete ascertainment procedure.
Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early‐onset sarcoidosis
Authors: Okafuji Ikuo , Nishikomori Ryuta , Kanazawa Nobuo , Kambe Naotomo , Fujisawa Akihiro , Yamazaki Shin , Saito Megumu , Yoshioka Takakazu , Kawai Tomoki , Sakai Hidemasa , Tanizaki Hideaki , Heike Toshio , Miyachi Yoshiki , Nakahata Tatsutoshi
Published: December 2008

Objective

Blau syndrome and its sporadic counterpart, early‐onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF‐κB activity predict the Blau syndrome/EOS clinical phenotype.

Methods

Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF‐κB activity, which was defined as the ratio of NF‐κB activity without a NOD2 ligand, muramyldipeptide, to NF‐κB activity with muramyldipeptide.

Results

All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand‐independent NF‐κB activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF‐κB activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment.

Conclusion

NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.
Genetic association of the major histocompatibility complex with rheumatoid arthritis implicates two non‐DRB1 loci
Authors: Vignal Charlotte , Bansal Aruna T. , Balding David J. , Binks Michael H. , Dickson Marion C. , Montgomery Doug S. , Wilson Anthony G.
Published: December 2008

Objective

The HLA–DRB1 locus within the major histocompatibility complex (MHC) at 6p21.3 has been identified as a susceptibility gene for rheumatoid arthritis (RA); however, there is increasing evidence of additional susceptibility genes in the MHC region. The aim of this study was to estimate their number and location.

Methods

A case–control study was performed involving 977 control subjects and 855 RA patients. The HLA–DRB1 locus was genotyped together with 2,360 single‐nucleotide polymorphisms in the MHC region. Logistic regression was used to detect DRB1‐independent effects.

Results

After adjusting for the effect of HLA–DRB1, 18 markers in 14 genes were strongly associated with RA (P < 10−4). Multivariate logistic regression analysis of these markers and DRB1 led to a model containing DRB1 plus the following 3 markers: rs4678, a nonsynonymous change in the VARS2L locus, ∼1.7 Mb telomeric of DRB1; rs2442728, upstream of HLA–B, ∼1.2 Mb telomeric of DRB1; and rs17499655, located in the 5′‐untranslated region of DQA2, only 0.1 Mb centromeric of DRB1. In‐depth investigation of the DQA2 association, however, suggested that it arose through cryptic linkage disequilibrium with an allele of DRB1. Two non–shared epitope alleles were also strongly associated with RA (P < 10−4): *0301 with anti– cyclic citrullinated peptide–negative RA and *0701 independently of autoantibody status.

Conclusion

These results confirm the polygenic contribution of the MHC to RA and implicate 2 additional non‐DRB1 susceptibility loci. The role of the HLA–DQ locus in RA has been a subject of controversy, but in our data, it appears to be spurious.
Novel markers of inflammation identified in tumor necrosis factor receptor–associated periodic syndrome (TRAPS) by transcriptomic analysis of effects of TRAPS‐associated tumor necrosis factor receptor type I mutations in an endothelial cell line
Authors: Rebelo Susana L. , Amel‐Kashipaz Mohammad R. , Radford Paul M. , Bainbridge Susan E. , Fiets Roel , Fang Johnny , McDermott Elizabeth M. , Powell Richard J. , Todd Ian , Tighe Patrick J.
Published: December 2008

Objective

To analyze the effects of tumor necrosis factor receptor–associated periodic syndrome (TRAPS)–associated mutant tumor necrosis factor receptor type I (TNFRI) expression in a cell type directly relevant to the inflammation in TRAPS, and to identify novel markers associated with mutant TNFRI expression.

Methods

Transcriptome analysis on 30,000 human genes was performed on SK‐Hep‐1 human endothelial cells transfected with either wild‐type (WT) or TRAPS‐associated mutant TNFRI. Quantitative reverse transcriptase–polymerase chain reaction and protein expression levels measured by enzyme‐linked immunosorbent assay verified transcriptional changes for selected genes both in supernatants from cells expressing mutant TNFRI and in patient plasma.

Results

Cells expressing mutant TNFRI showed up‐regulation of multiple proinflammatory genes relative to WT transfectants, including genes for pentraxin 3, granulocyte–macrophage colony‐stimulating factor, granulocyte colony‐stimulating factor, CCL2, and CCL5, which were also expressed as proteins. In addition, the expression of most of these markers was increased in the plasma and peripheral blood mononuclear cells from TRAPS patients relative to those from healthy controls. The cysteine mutations (C33Y and C52F), which are associated with a more severe clinical phenotype, induced more genes than the low‐penetrance mutation R92Q, which is associated with a milder phenotype. The expression of most genes was induced by a death domain (DD)–dependent mechanism, since they were not induced by expression of TNFRI mutants with an inactivated DD.

Conclusion

TRAPS‐associated TNFRI mutants induce the expression of multiple genes encoding inflammatory molecules, cellular receptors, transcription factors, and regulators of apoptosis in endothelial cells that require the cytoplasmic signaling properties of the receptor. Different mutants have specific expression profiles, indicating mutation‐specific effects. The expression of some of these markers was also elevated in samples from TRAPS patients.
Independent association of rheumatoid arthritis with increased left ventricular mass but not with reduced ejection fraction
Authors: Rudominer Rebecca L. , Roman Mary J. , Devereux Richard B. , Paget Stephen A. , Schwartz Joseph E. , Lockshin Michael D. , Crow Mary K. , Sammaritano Lisa , Levine Daniel M. , Salmon Jane E.
Published: December 2008

Objective

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with premature atherosclerosis, vascular stiffening, and heart failure. This study was undertaken to investigate whether RA is associated with underlying structural and functional abnormalities of the left ventricle (LV).

Methods

Eighty‐nine RA patients without clinical cardiovascular disease and 89 healthy matched controls underwent echocardiography, carotid ultrasonography, and radial tonometry to measure arterial stiffness. RA patients and controls were similar in body size, hypertension and diabetes status, and cholesterol level.

Results

LV diastolic diameter (4.92 cm versus 4.64 cm; P < 0.001), mass (136.9 gm versus 121.7 gm; P = 0.004 or 36.5 versus 32.9 gm/m2.7; P = 0.01), ejection fraction (71% versus 67%; P < 0.001), and prevalence of LV hypertrophy (18% versus 6.7%; P = 0.023) were all higher among RA patients versus controls. In multivariate analysis, presence of RA was an independent correlate of LV mass (P = 0.004). Furthermore, RA was independently associated with presence of LV hypertrophy (odds ratio 4.14 [95% confidence interval 1.24, 13.80], P = 0.021). Among RA patients, age at diagnosis and disease duration were independently related to LV mass. RA patients with LV hypertrophy were older and had higher systolic pressure, damage index scores, C‐reactive protein levels, homocysteine levels, and arterial stiffness compared with those without LV hypertrophy.

Conclusion

The present results demonstrate that RA is associated with increased LV mass. Disease duration is independently related to increased LV mass, suggesting a pathophysiologic link between chronic inflammation and LV hypertrophy. In contrast, LV systolic function is preserved in RA patients, indicating that systolic dysfunction is not an intrinsic feature of RA.
Systems biology analysis of sjögren's syndrome and mucosa‐associated lymphoid tissue lymphoma in parotid glands
Authors: Hu Shen , Zhou Michael , Jiang Jiang , Wang Jianghua , Elashoff David , Gorr Sven , Michie Sara A. , Spijkervet Fred K. L. , Bootsma Hendrika , Kallenberg Cees G. M. , Vissink Arjan , Horvath Steve , Wong David T.
Published: December 2008

Objective

To identify key target genes and activated signaling pathways associated with the pathogenesis of Sjögren's syndrome (SS) by conducting a systems analysis of parotid glands manifesting primary SS or primary SS/mucosa‐associated lymphoid tissue (MALT) lymphoma phenotypes.

Methods

A systems biology approach was used to analyze parotid gland tissue samples obtained from patients with primary SS, patients with primary SS/MALT lymphoma, and subjects without primary SS (non–primary SS controls). The tissue samples were assessed concurrently by gene‐expression microarray profiling and proteomics analysis, followed by weighted gene‐coexpression network analysis.

Results

Gene‐coexpression modules related to primary SS and primary SS/MALT lymphoma were significantly enriched with genes known to be involved in the immune/defense response, apoptosis, cell signaling, gene regulation, and oxidative stress. Detailed functional pathway analyses indicated that primary SS–associated modules were enriched with genes involved in proteasome degradation, apoptosis, signal peptides of the class I major histocompatibility complex (MHC), complement activation, cell growth and death, and integrin‐mediated cell adhesion, while primary SS/MALT lymphoma–associated modules were enriched with genes involved in translation, ribosome biogenesis and assembly, proteasome degradation, class I MHC signal peptides, the G13 signaling pathway, complement activation, and integrin‐mediated cell adhesion. Combined analyses of gene expression and proteomics data implicated 6 highly connected “hub” genes for distinguishing primary SS from non–primary SS, and 8 hub genes for distinguishing primary SS/MALT lymphoma from primary SS.

Conclusion

Systems biology analyses of the parotid glands from patients with primary SS and those with primary SS/MALT lymphoma revealed pathways and molecular targets associated with disease pathogenesis. The identified gene modules/pathways provide further insights into the molecular mechanisms of primary SS and primary SS/MALT lymphoma. The identified disease‐hub genes represent promising targets for therapeutic intervention, diagnosis, and prognosis.
Effect of interleukin‐1β on osteogenic protein 1–induced signaling in adult human articular chondrocytes
Authors: Elshaier Amel M. , Hakimiyan Arnavaz A. , Rappoport Lev , Rueger David C. , Chubinskaya Susan
Published: December 2008

Objective

Two major receptor‐activated Smad (R‐Smad) signaling pathways, bone morphogenetic protein (BMP) and MAPK, were examined in a model of interleukin‐1β (IL‐1β)–induced cartilage degeneration to investigate the effect of IL‐1β on osteogenic protein 1 (OP‐1) signaling in adult human articular chondrocytes.

Methods

Chondrocytes from the ankles of 26 normal human donors were cultured in high‐density monolayers in serum‐free medium. The effect of IL‐1β on BMP receptors was studied by reverse transcription–polymerase chain reaction and flow cytometry. Phosphorylation of R‐Smads was tested in cells treated with IL‐1β (10 ng/ml), OP‐1 (100 ng/ml), or the combination of IL‐1β and OP‐1. Cell lysates were analyzed by Western blotting with polyclonal antibodies against 2 R‐Smad phosphorylation sites (BMP‐ and MAPK‐mediated) or with total, nonphosphorylated R‐Smad as a control. To identify which MAPKs play a role in IL‐1β activation of the linker region, chondrocytes were preincubated with specific MAPK inhibitors (PD98059 for MAP/ERK, SP600125 for JNK, and SB203580 for p38).

Results

IL‐1β reduced the number of activin receptor–like kinase 2 (ALK‐2) and ALK‐3 receptors, inhibited expression of Smad1 and Smad6, delayed and prematurely terminated the onset of OP‐1–mediated R‐Smad phosphorylation, and affected nuclear translocation of R‐Smad/Smad4 complexes. The alternative phosphorylation of R‐Smad in the linker region via the MAPK pathway (primarily p38 and JNK) was observed to be a possible mechanism through which IL‐1β offsets OP‐1 signaling and the response to OP‐1. Conversely, OP‐1 was found to directly inhibit phosphorylation of p38.

Conclusion

These findings describe new mechanisms of the crosstalk between OP‐1 and IL‐1β in chondrocytes. The study also identifies potential targets for therapeutic interventions in the treatment of cartilage‐degenerative processes.
Association of the TRAF1/C5 locus with increased mortality, particularly from malignancy or sepsis, in patients with rheumatoid arthritis
Authors: Panoulas Vasileios F. , Smith Jacqueline P. , Nightingale Peter , Kitas George D.
Published: December 2008

Objective

Recent genome‐wide association studies have identified TRAF1/C5 as a rheumatoid arthritis (RA) susceptibility locus. Tumor necrosis factor receptor–associated factor 1 (TRAF1) has been implicated in the regulation of antiapoptotic pathways, whereas C5 has a well‐established role in defense against infection. The purpose of this study was to examine the association of the TRAF1/C5 locus with death in patients with RA.

Methods

Genomic DNA samples were collected from a prospective cohort of 400 RA patients. TRAF1/C5 rs3761847 was identified using real‐time polymerase chain reaction and melting curve analyses. The association of TRAF1/C5 rs3761847 alleles with the risk of death was assessed using Cox proportional hazards regression analyses.

Results

TRAF1/C5 rs3761847 GG homozygote status was associated with an increased risk of death (hazard ratio 3.96 [95% confidence interval 1.24–12.6], P = 0.020) as compared with AA homozygote status. The excess mortality was attributed to deaths due to malignancies and sepsis but not cardiovascular disease (CVD). This polymorphism was one of the strongest predictors of death in RA (for TRAF1/C5 GG versus AA, hazard ratio 3.85 [95% confidence interval 1.18–12.59], P = 0.026) alongside the erythrocyte sedimentation rate, triglyceride level, prednisolone use, and age.

Conclusion

The risk of death in RA is increased in TRAF1/C5 rs3761847 GG homozygotes and appears to be independent of RA activity and severity as well as comorbidities relevant to CVD. If this finding is replicated in future studies, TRAF1/C5 genotyping could identify patients at increased risk of death, particularly death due to malignancy or sepsis.
Activation of synoviolin promoter in rheumatoid synovial cells by a novel transcription complex of interleukin enhancer binding factor 3 and GA binding protein α
Authors: Izumi Toshihiko , Fujii Ryoji , Izumi Tomonori , Nakazawa Minako , Yagishita Naoko , Tsuchimochi Kaneyuki , Yamano Yoshihisa , Sato Tomoo , Fujita Hidetoshi , Aratani Satoko , Araya Natsumi , Azakami Kazuko , Hasegawa Daisuke , Kasaoka Shunji , Tsuruta Ryosuke , Yokouti Masahiro , Ijiri Kosei , Beppu Moroe , Maruyama Ikuro , Nishioka Kusuki , Maekawa Tsuyoshi , Komiya Setsuro , Nakajima Toshihiro
Published: December 2008

Objective

Synoviolin is an E3 ubiquitin ligase, and its overexpression is implicated in the pathogenesis of rheumatoid arthritis (RA). We reported previously that Ets binding site 1 (EBS‐1) within the synoviolin promoter is crucial for the expression of synoviolin, and GA binding protein (GABP) binds to this site. This study was undertaken to elucidate the precise mechanisms of transcriptional regulation via EBS‐1.

Methods

We performed purification and identification of complex components that bind to EBS‐1 and inspected their contributions to the transcriptional regulation of synoviolin in rheumatoid synovial cells. We biochemically purified proteins that had EBS‐1 binding activity and identified the proteins using liquid chromatography tandem mass spectrometry analysis. The identified proteins were verified to recruit and form the complex on EBS‐1 using electrophoretic mobility shift assay and coimmunoprecipitation assay. Furthermore, their transcription activities were tested by reporter assays and RNA interference experiments.

Results

We identified interleukin enhancer binding factor 3 (ILF‐3) as a novel factor in the complex. ILF‐3 was demonstrated to activate the synoviolin promoter via association with GABPα in rheumatoid synovial cells. In addition, further activation was observed with ILF‐2 and GABPβ, previously reported interactants of ILF‐3 and GABPα, respectively. Moreover, ILF‐3–knockdown experiments showed reduced expression of the synoviolin gene.

Conclusion

Our findings indicate that ILF‐3, which has been known to regulate IL‐2 expression in T cells, up‐regulates synoviolin expression with GABPα in rheumatoid synovial cells. ILF‐3 might be a target for RA treatment through its effect on IL‐2 in T cells and synoviolin in rheumatoid synovial cells.
The chromosome 7q region association with rheumatoid arthritis in females in a british population is not replicated in a North American case–control series
Authors: Korman Benjamin D. , Seldin Michael F. , Taylor Kimberly E. , Le Julie M. , Lee Annette T. , Plenge Robert M. , Amos Christopher I. , Criswell Lindsey A. , Gregersen Peter K. , Kastner Daniel L. , Remmers Elaine F.
Published: December 2008

Objective

The single‐nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported to be sexually dimorphic marker for rheumatoid arthritis (RA) susceptibility in a British population. We sought to replicate this finding and to better characterize susceptibility alleles in the region in a North American population.

Methods

DNA from 2 North American collections of RA patients and controls (1,605 cases and 2,640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately, contrasting male cases with male controls and female cases with female controls. Principal components analysis (EigenStrat) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples for which there were whole‐genome SNP data (772 cases and 1,213 controls).

Results

We failed to replicate an association of the 7q region with RA. Initially, rs11761231 showed evidence for association with RA in the North American Rheumatoid Arthritis Consortium (NARAC) collection (P = 0.0073), and rs11765576 showed association with RA in both the NARAC (P = 0.038) and RA replication (P = 0.0013) collections. These markers also exhibited sex differentiation. However, in the whole‐genome subset, neither SNP showed significant association with RA after correction for population stratification.

Conclusion

While 2 SNPs on chromosome 7q appeared to be associated with RA in a North American cohort, the significance of this finding did not withstand correction for population substructure. Our results emphasize the need to carefully account for population structure to avoid false‐positive disease associations.
Quadriceps strength and the risk of cartilage loss and symptom progression in knee osteoarthritis
Authors: Amin Shreyasee , Baker Kristin , Niu Jingbo , Clancy Margaret , Goggins Joyce , Guermazi Ali , Grigoryan Mikayel , Hunter David J. , Felson David T.
Published: December 2008

Objective

To determine the effect of quadriceps strength in individuals with knee osteoarthritis (OA) on loss of cartilage at the tibiofemoral and patellofemoral joints (assessed by magnetic resonance imaging [MRI]) and on knee pain and function.

Methods

We studied 265 subjects (154 men and 111 women, mean ± SD age 67 ± 9 years) who met the American College of Rheumatology criteria for symptomatic knee OA and who were participating in a prospective, 30‐month natural history study of knee OA. Quadriceps strength was measured at baseline, isokinetically, during concentric knee extension. MRI of the knee at baseline and at 15 and 30 months was used to assess cartilage loss at the tibiofemoral and patellofemoral joints, with medial and lateral compartments assessed separately. At baseline and at followup visits, knee pain was assessed using a visual analog scale, and physical function was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index.

Results

There was no association between quadriceps strength and cartilage loss at the tibiofemoral joint. Results were similar in malaligned knees. However, greater quadriceps strength was protective against cartilage loss at the lateral compartment of the patellofemoral joint (for highest versus lowest tertile of strength, odds ratio 0.4 [95% confidence interval 0.2, 0.9]). Those with greater quadriceps strength had less knee pain and better physical function over followup (P< 0.001).

Conclusion

Greater quadriceps strength had no influence on cartilage loss at the tibiofemoral joint, including in malaligned knees. We report for the first time that greater quadriceps strength protected against cartilage loss at the lateral compartment of the patellofemoral joint, a finding that requires confirmation. Subjects with greater quadriceps strength also had less knee pain and better physical function over followup.
Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis
Authors: Akhmetshina Alfiya , Venalis Paulius , Dees Clara , Busch Nicole , Zwerina Jochen , Schett Georg , Distler Oliver , Distler Jörg H. W.
Published: December 2008

Objective

Imatinib is a small‐molecule tyrosine kinase inhibitor capable of selective, dual inhibition of the transforming growth factor β and platelet‐derived growth factor (PDGF) pathways. Imatinib has previously been shown to prevent the development of inflammation‐driven experimental fibrosis when treatment was initiated before administration of the profibrotic stimulus. The aim of this study was to confirm the efficacy of imatinib in a murine model of systemic sclerosis (SSc) that is less driven by inflammation and to investigate whether imatinib is also effective for the treatment of established fibrosis.

Methods

The tight skin 1 (TSK‐1) mouse model of SSc was used to evaluate the antifibrotic effects of imatinib in a genetic model of the later stages of SSc. In addition, the efficacy of imatinib for the treatment of preestablished fibrosis was analyzed in a modified model of bleomycin‐induced dermal fibrosis in which the application of bleomycin was prolonged and the onset of treatment was late.

Results

Treatment with imatinib reduced dermal and hypodermal thickening in TSK‐1 mice and prevented the differentiation of resting fibroblasts into myofibroblasts. In the model of preestablished dermal fibrosis, imatinib not only stopped further progression of fibrosis but also induced regression of preexisting dermal fibrosis, with a reduction in dermal thickness below pretreatment levels.

Conclusion

These results indicate that combined inhibition of the tyrosine kinase c‐Abl and PDGF receptor might be effective in the later, less inflammatory stages of SSc and for the treatment of established fibrosis. Thus, imatinib might be an interesting candidate for clinical trials in patients with longstanding disease and preexisting tissue fibrosis.
Requirement of transforming growth factor β–activated kinase 1 for transforming growth factor β–induced α‐smooth muscle actin expression and extracellular matrix contraction in fibroblasts
Authors: Shi‐Wen Xu , Parapuram Sunil K. , Pala Daphne , Chen Yunliang , Carter David E. , Eastwood Mark , Denton Christopher P. , Abraham David J. , Leask Andrew
Published: December 2008

Objective

Fibrosis is believed to occur through normal tissue remodeling failing to terminate. Tissue repair intimately involves the ability of fibroblasts to contract extracellular matrix (ECM), and enhanced ECM contraction is a hallmark of fibrotic cells in various conditions, including scleroderma. Some fibrogenic transcriptional responses to transforming growth factor β (TGFβ), including α‐smooth muscle actin (α‐SMA) expression and ECM contraction, require focal adhesion kinase/Src (FAK/Src). The present study was undertaken to assess whether TGFβ‐activated kinase 1 (TAK1) acts downstream of FAK/Src to mediate fibrogenic responses in fibroblasts.

Methods

We used microarray, real‐time polymerase chain reaction, Western blot, and collagen gel contraction assays to assess the ability of wild‐type and TAK1‐knockout fibroblasts to respond to TGFβ1.

Results

The ability of TGF to induce TAK1 was blocked by the FAK/Src inhibitor PP2. JNK phosphorylation in response to TGFβ1 was impaired in the absence of TAK1. TGFβ could not induce matrix contraction or expression of a group of fibrotic genes, including α‐SMA, in the absence of TAK1.

Conclusion

These results suggest that TAK1 operates downstream of FAK/Src in mediating fibrogenic responses and that targeting of TAK1 may be a viable antifibrotic strategy in the treatment of certain disorders, including scleroderma.
Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus
Authors: Bertsias George K. , Nakou Magda , Choulaki Christianna , Raptopoulou Amalia , Papadimitraki Eva , Goulielmos George , Kritikos Herakles , Sidiropoulos Prodromos , Tzardi Maria , Kardassis Dimitris , Mamalaki Clio , Boumpas Dimitrios T.
Published: December 2008

Objective

A putative regulatory intronic polymorphism (PD1.3) in the programmed death 1 (PD‐1) gene, a negative regulator of T cells involved in peripheral tolerance, is associated with increased risk for systemic lupus erythematosus (SLE). We undertook this study to determine the expression and function of PD‐1 in SLE patients.

Methods

We genotyped 289 SLE patients and 256 matched healthy controls for PD1.3 by polymerase chain reaction–restriction fragment length polymorphism analysis. Expression of PD‐1 and its ligand, PDL‐1, was determined in peripheral blood lymphocytes and in renal biopsy samples by flow cytometry and immunohistochemistry. A crosslinker of PD‐1 was used to assess its effects on anti‐CD3/anti‐CD28–induced T cell proliferation and cytokine production.

Results

SLE patients had an increased frequency of the PD1.3 polymorphism (30.1%, versus 18.4% in controls; P = 0.006), with the risk A allele conferring decreased transcriptional activity in transfected Jurkat cells. Patients homozygous for PD1.3—but not patients heterozygous for PD1.3—had reduced basal and induced PD‐1 expression on activated CD4+ T cells. In autologous mixed lymphocyte reactions (AMLRs), SLE patients had defective PD‐1 induction on activated CD4+ cells; abnormalities were more pronounced among homozygotes. PD‐1 was detected within the glomeruli and renal tubules of lupus nephritis patients, while PDL‐1 was expressed by the renal tubules of both patients and controls. PD‐1 crosslinking suppressed proliferation and cytokine production in both normal and lupus T cells; addition of serum from patients with active SLE significantly ameliorated this effect on proliferation.

Conclusion

SLE patients display aberrant expression and function of PD‐1 attributed to both direct and indirect effects. The expression of PD‐1/PDL‐1 in renal tissue and during AMLRs suggests an important role in regulating peripheral T cell tolerance.
Identification of the core element responsive to runt‐related transcription factor 2 in the promoter of human type x collagen gene
Authors: Higashikawa Akiro , Saito Taku , Ikeda Toshiyuki , Kamekura Satoru , Kawamura Naohiro , Kan Akinori , Oshima Yasushi , Ohba Shinsuke , Ogata Naoshi , Takeshita Katsushi , Nakamura Kozo , Chung Ung‐Il , Kawaguchi Hiroshi
Published: December 2008

Objective

Type X collagen and runt‐related transcription factor 2 (RUNX‐2) are known to be important for chondrocyte hypertrophy during skeletal growth and repair and development of osteoarthritis (OA) in mice. Aiming at clinical application, this study was undertaken to investigate transcriptional regulation of human type X collagen by RUNX‐2 in human cells.

Methods

Localization of type X collagen and RUNX‐2 was determined by immunohistochemistry, and their functional interaction was examined in cultured mouse chondrogenic ATDC‐5 cells. Promoter activity of the human type X collagen gene (COL10A1) was examined in human HeLa, HuH7, and OUMS27 cells transfected with a luciferase gene containing a 4.5‐kb promoter and fragments. Binding to RUNX‐2 was examined by electrophoretic mobility shift assay and chromatin immunoprecipitation.

Results

RUNX‐2 and type X collagen were co‐localized in mouse limb cartilage and bone fracture callus. Gain and loss of function of RUNX‐2 revealed that RUNX‐2 is essential for type X collagen expression and terminal differentiation of chondrocytes. Human COL10A1 promoter activity was enhanced by RUNX‐2 alone and more potently by RUNX‐2 in combination with the coactivator core‐binding factor β in all 3 human cell lines examined. Deletion, mutagenesis, and tandem repeat analyses identified the core responsive element as the region between −89 and −60 bp (termed the hypertrophy box [HY box]), which showed specific binding to RUNX‐2. Other putative RUNX‐2 binding motifs in the human COL10A1 promoter did not respond to RUNX‐2 in human cells.

Conclusion

Our findings indicate that the HY box is the core element responsive to RUNX‐2 in human COL10A1 promoter. Studies on molecular networks related to RUNX‐2 and the HY box will lead to treatments of skeletal growth retardation, bone fracture, and OA.
Pneumomediastinum in interstitial lung disease associated with dermatomyositis and polymyositis
Authors: Le Goff Benoit , Chérin Patrick , Cantagrel Alain , Gayraud Martine , Hachulla Eric , Laborde Fyriel , Papo Thomas , Sibilia Jean , Zabraniecki Laurent , Ravaud Philippe , Puéchal Xavier
Published: December 2008

Objective

Spontaneous pneumomediastinum is a rare complication of dermatomyositis (DM) and polymyositis (PM). The aim of this study was to characterize this complication and determine its prognostic factors.

Methods

We retrospectively collected a multicenter series of PM/DM cases complicated by pneumomediastinum. We analyzed all published cases and combined those that were exploitable with ours for an investigation of the factors associated with poor survival.

Results

We collected 11 PM/DM cases complicated by interstitial lung disease and pneumomediastinum. Five of the 9 DM patients had clinically amyopathic DM without muscle weakness and high serum creatine kinase levels. The outcome was favorable in 7 of these patients and 6 had no sequelae. In total, ∼25% of our patients of the 21 analyzable cases studied died within 1 month. With a median followup of 240 days, the cumulative estimated Kaplan‐Meier survival rate was 64% at 1 year and 55% at 2 years. Poor survival was associated with absence of muscle weakness (P = 0.02), initial low vital capacity (P = 0.006), and initial low carbon monoxide diffusion capacity (P = 0.04).

Conclusion

In this first large series of patients with connective tissue disease complicated by pneumomediastinum to be reported, most patients had DM and half amyopathic DM, as in previous reports. Pneumomediastinum may occur before DM diagnosis and may thus reveal DM with minimal or no muscle involvement. Death was associated with an absence of muscle weakness and severe pulmonary involvement before the onset of pneumomediastinum. Corticosteroids and immunosuppressive therapy can result in complete recovery, as in half our cases.
Helix‐coil energetics for helix formers and breakers reflect context and temperature: Mutants of helically robust, guest‐sensitive homopeptide hosts
Authors: Nasr Khaled A. , Schubert Christian R. , Török Marianna , Kennedy Robert J. , Kemp Daniel S.
Published: December 2008

The natural amino acids are primarily helix breakers at the low assignment temperatures characteristic of many studies, but recent genomic analyses of thermophilic proteins suggest that at high temperatures, some breakers may become strong helix formers. Moreover, the breaker/former inventory has not been previously characterized at the physiologically relevant temperature of 37°C. The versatility of 13CO NMR chemical shifts as helicity reporters allows construction of two mutant peptide series, tailored to expand the range of temperature assignments for helical propensities and derived from the core hosts tL‐Ala9XxxAla9‐tL and tL‐AlaNva4XxxNva4Ala9‐tL, Nva = norvaline. For three limiting guests Xxx, the helix former Nva and the breakers Gly and Pro, we report wXxx[T] assignments at seven temperatures from 2 to 80°C, validating our reasoning and paving the way for assignment of a definitive wXxx[T] data‐base. © 2008 Wiley Periodicals, Inc. Biopolymers 91: 311–320, 2009.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Shaping the Polypropionate Biosynthesis in the Solar‐Powered Mollusc Elysia viridis
Authors: Cutignano Adele , Cimino Guido , Villani Guido , Fontana Angelo
Published: December 2008

Polypropionates that incorporate pyrones are a family of polyketides featuring the chemistry of a few marine molluscs capable of phototrophic CO2 fixation as a result of storing viable symbiotic chloroplasts in their bodies. The role and origin of these molecules is poorly investigated, although the unusual biological activities and chemistry of these natural products have recently received renewed interest. Here, we report the results of in vivo studies on production of γ‐pyrone‐containing polypropionates in the Mediterranean mollusc Elysia viridis. Biosynthesis of the metabolites in the sacoglossan is shown to proceed through condensation of eight intact C3 units by polyketide synthase assembly. LC–MS and NMR spectroscopic studies demonstrate that the process involves a pyrone tetraene (10) as key intermediate, whereas the levels of the final polypropionates (6, 7 and 9) are related to each other and show a significant dependence upon light conditions.
Effect of Doped Transition Metal on Reversible Hydrogen Release/Uptake from NaAlH4
Authors: Liu Jianjun , Han You , Ge Qingfeng
Published: December 2008

Storage facility: A dihydrogen complex formed in transition‐metal‐doped NaAlH4 was found to play important roles in hydrogen release/uptake (see figure). Electronic structure analysis revealed that the electron transfer between hydrogen and Al groups was mediated by the d orbitals of transition metals. Hydrogen release/uptake from the transition‐metal‐doped NaAlH4 was accompanied by an exchange of AlH and HH bond ligands through σ‐bond metathesis.

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Periodic density functional theory calculations with plane‐wave basis set and projector‐augmented wave potentials have been carried out to investigate the stability and hydrogen interaction in the NaAlH4(001) surfaces doped with 3d transition‐metal (TM) elements. A complex structure, TMAl3H12, in which the TM atom occupies the interstitial position formed from three AlH4− groups, is the most stable structure for TM=Sc to Co. The stability of the complex structure, as well as the hydrogen desorption energies from different positions of the complex structure, was found to follow the 18‐electron rule in general. The electron‐deficient TMAl3Hx tends to get more electrons by coordinating with the surrounding AlH bonds and HH bond, or by losing the “outside” hydrogen atoms. On the other hand, the electron‐rich complex loses its excess electrons easily by releasing AlHx, which resulted in the formation of a new catalytic center, or by desorbing H2. By cycling between the electron‐deficient and electron‐rich states, TMAl3Hx acted as an active center in reversible hydrogen release/uptake processes. Electronic structure analysis revealed that the electron transfer between hydrogen and Al groups mediated by the d orbitals of TMs played important roles in hydrogen release/uptake from alanate‐based materials. The exchange of ligands can be described as a σ‐bond metathesis process catalyzed by transition metals through a dihydrogen complex. Early transition metals are more efficient to reduce hydrogen desorption energy and break HH and AlH bonds as a result of balanced electron‐accepting/backdonating abilities, making them better candidates as catalysts. The present analyses are consistent with the experimental observations.
Bi2O3 Hierarchical Nanostructures: Controllable Synthesis, Growth Mechanism, and their Application in Photocatalysis
Authors: Zhou Lin , Wang Wenzhong , Xu Haolan , Sun Songmei , Shang Meng
Published: December 2008

Flower power: Unique 3D flower‐like Bi2O3 hierarchical nanostructures were synthesized using a mild aqueous template‐free method (see figure). By introducing VO3− into the reaction system, which mediated the nucleation and growth of Bi2O3, the in situ self‐assembly of 3D hierarchitectures from 2D nanosheets has been realized.

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By introducing VO3− into the reaction system, uniform hierarchical nanostructures of Bi2O3 have been successfully synthesized by a template‐free aqueous method at 60–80 °C for 6 h. The as‐prepared hierarchitectures are composed of 2D nanosheets, which intercross with each other. Based on the electron microscope observations, the growth of such hierarchitectures has been proposed as an Ostwald ripening process followed by self‐assembly. The nucleation, growth, and self‐assembly of Bi2O3 nanosheets could be readily tuned, which brought different morphologies and microstructures to the final products. Pore‐size distribution analysis revealed that both mesopores and macropores existed in the product. UV‐vis spectroscopy was employed to estimate the band gap energies of the hierarchical nanostructures. The photocatalytic activities of as‐prepared Bi2O3 hierarchitectures were 6–10 times higher than that of the commercial sample, which was evaluated by the degradation of RhB dye under visible light irradiation (λ>420 nm).
Chemoselective Capture of Glycans for Analysis on Gold Nanoparticles: Carbohydrate Oxime Tautomers Provide Functional Recognition by Proteins
Authors: Thygesen Mikkel B. , Sauer Jørgen , Jensen Knud J.
Published: December 2008

Open or closed: N‐Glycosyl oxyamine versus open‐chain glycosyl oxime is the key to protein recognition on glyconanoparticles. Unprotected glycans are captured by oxime formation with a novel bifunctional reagent and the resulting glycan‐linker conjugates are anchored to gold nanoparticles (AuNPs). These glyconanoparticles maintain the structural integrity of glycans in the study of protein–carbohydrate interactions (see figure).

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Nanoparticles functionalized with glycans are emerging as powerful solid‐phase chemical tools for the study of protein–carbohydrate interactions using nanoscale properties for detection of binding events. Methods or reagents that enable the assembly of glyconanoparticles from unprotected glycans in two consecutive chemoselective steps with meaningful display of the glycan are highly desirable. Here, we describe a novel bifunctional reagent that 1) couples to glycans by oxime formation in solution, 2) aids in purification through a lipophilic trityl tag, and 3) after deprotection then couples to gold nanoparticles through a thiol. NMR studies revealed that these oximes exist as both the open‐chain and N‐glycosyl oxy‐amine tautomers. Glycan‐linker conjugates were coupled through displacement of ligands from preformed, citrate‐stabilized gold nanoparticles. Recognition of these glycans by proteins was studied with a lectin, concanavalin A (ConA), in an aggregation assay and with a processing enzyme and glucoamylase (GA). We demonstrate that the presence of the N‐glycosyl oxy‐amines clearly enables functional recognition in sharp contrast to the corresponding reduced oxy‐amines. This concept is then realized in a novel reagent, which should facilitate nanoglycobiology by enabling the operationally simple capture of glycans and their biologically meaningful display.