bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of cathepsin K deficiency on airway development and TGF-β1 degradation
Authors: Zhang Dongwei , Leung Nelson , Weber Ekkehard , Saftig Paul , Brömme Dieter 
Published: May 2011

AbstractBackgroundCathepsin K, a cysteine protease predominantly expressed in osteoclasts, is a major drug target for the treatment of osteoporosis. Recent findings, however, indicate that cathepsin K is also involved in non-skeletal metabolism. The development of fibrotic phenotypes in lung and skin is a concern for cathepsin K inhibitors presently evaluated in clinical trials. Cathepsin K is expressed in lung tissue and has been implicated in lung fibrosis. However, little is known about the role of cathepsin K in airway development and its effect on TGF-β1 degradation.MethodsWe investigated the effects of cathepsin K-deficiency on alterations in airway integrity, extracellular matrix composition, and TGF-β1 expression and degradation. Lung homogenates of wild-type and cathepsin K-deficient mice were used to evaluate their contents of collagen, glycosaminoglycans, and TGF-β1. The accessibility of TGF-β1 to cathepsin K-mediated degradation was determinedin vitroand lung fibroblast proliferations in wild-type and cathepsin K-deficient cells were evaluated.ResultsLung airway cathepsin K expression in wild-type mice remained constant between 1 and 6 months of age and the airway integrity was maintained. In contrast, after 2 months of age, allCtsk-/-mice demonstrated increased airway epithelium thickness by 16-28%, a lower structural airway integrity (1-2 score units lower), elevated cytokeratin expression of 12%, increased α-actin and vimentin expression by 50% and 70%, increased area of smooth muscle cells by 15%, elevated hydroxyproline and GAGs content by 20% and 25%, and increased TGF-β1 expression by 25%. TGF-β1 proved an efficient substrate of cathepsin K and TGF-β1 protein content in lung was increased by a potent cathepsin inhibitor. Lung fibroblasts fromCtsk-/-mice after TGF-β1 treatment showed increased proliferation rates, increased levels of TGF-β1 by 30%, and increased ECM secretion.ConclusionThis study suggests that airway development is partly regulated by cathepsin K and that its expression contributes to the maintenance of the airway structural integrity. The anticipated use of therapeutic cathepsin K inhibitors needs to take potential changes in human lungs into consideration.
Dermatan sulfate in tunicate phylogeny: Order-specific sulfation pattern and the effect of [→4IdoA(2-Sulfate)β-1→3GalNAc(4-Sulfate)β-1→] motifs in dermatan sulfate on heparin cofactor II activity
Authors: Kozlowski Eliene O , Lima Paula C , Vicente Cristina P , Lotufo Tito , Bao Xingfeng , Sugahara Kazuyuki , Pavão Mauro SG 
Published: May 2011

Abstract

Background
Previously, we have reported the presence of highly sulfated dermatans in solitary ascidians from the orders Phlebobranchia (Phallusia nigra) and Stolidobranchia (Halocynthia pyriformis and Styela plicata). Despite the identical disaccharide backbone, consisting of [→4IdoA(2S)β-1→3GalNAcβ-1→], those polymers differ in the position of sulfation on the N-Acetyl galactosamine, which can occur at carbon 4 or 6. We have shown that position rather than degree of sulfation is important for heparin cofactor II activity. As a consequence, 2,4- and 2,6-sulfated dermatans have high and low heparin cofactor II activities, respectively. In the present study we extended the disaccharide analysis of ascidian dermatan sulfates to additional species of the orders Stolidobranchia (Herdmania pallida, Halocynthia roretzi) and Phlebobranchia (Ciona intestinalis), aiming to investigate how sulfation evolved within Tunicata. In addition, we analysed how heparin cofactor II activity responds to dermatan sulfates containing different proportions of 2,6- or 2,4-disulfated units.

Results
Disaccharide analyses indicated a high content of disulfated disaccharide units in the dermatan sulfates from both orders. However, the degree of sulfation decreased from Stolidobranchia to Phlebobranchia. While 76% of the disaccharide units in dermatan sulfates from stolidobranch ascidians are disulfated, 53% of disulfated disaccharides are found in dermatan sulfates from phlebobranch ascidians. Besides this notable difference in the sulfation degree, dermatan sulfates from phlebobranch ascidians contain mainly 2,6-sulfated disaccharides whereas dermatan sulfate from the stolidobranch ascidians contain mostly 2,4-sulfated disaccharides, suggesting that the biosynthesis of dermatan sulfates might be differently regulated during tunicates evolution. Changes in the position of sulfation on N-acetylgalactosamine in the disaccharide [→4IdoA(2-Sulfate)β-1→3GalNAcβ-1→] modulate heparin cofactor II activity of dermatan sulfate polymers. Thus, high and low heparin cofactor II stimulating activity is observed in 2,4-sulfated dermatan sulfates and 2,6-sulfated dermatan sulfates, respectively, confirming the clear correlation between the anticoagulant activities of dermatan sulfates and the presence of 2,4-sulfated units.

Conclusions
Our results indicate that in ascidian dermatan sulfates the position of sulfation on the GalNAc in the disaccharide [→4IdoA(2S)β-1→3GalNAcβ-1→] is directly related to the taxon and that the 6-O sulfation is a novelty apparently restricted to the Phlebobranchia. We also show that the increased content of [→4IdoA(2S)β-1→3GalNAc(4S)β-1→] disaccharide units in dermatan sulfates from Stolidobranchia accounts for the increased heparin cofactor II stimulating activity.
Evidence of association between Nucleosome Occupancy and the Evolution of Transcription Factor Binding Sites in Yeast
Authors: Swamy Krishna BS , Chu Wen-Yi , Wang Chun-Yi , Tsai Huai-Kuang , Wang Daryi 
Published: May 2011

Abstract

Background
Divergence of transcription factor binding sites is considered to be an important source of regulatory evolution. The associations between transcription factor binding sites and phenotypic diversity have been investigated in many model organisms. However, the understanding of other factors that contribute to it is still limited. Recent studies have elucidated the effect of chromatin structure on molecular evolution of genomic DNA. Though the profound impact of nucleosome positions on gene regulation has been reported, their influence on transcriptional evolution is still less explored. With the availability of genome-wide nucleosome map in yeast species, it is thus desirable to investigate their impact on transcription factor binding site evolution. Here, we present a comprehensive analysis of the role of nucleosome positioning in the evolution of transcription factor binding sites.

Results
We compared the transcription factor binding site frequency in nucleosome occupied regions and nucleosome depleted regions in promoters of old (orthologs among Saccharomycetaceae) and young (Saccharomyces specific) genes; and in duplicate gene pairs. We demonstrated that nucleosome occupied regions accommodate greater binding site variations than nucleosome depleted regions in young genes and in duplicate genes. This finding was confirmed by measuring the difference in evolutionary rates of binding sites in sensu stricto yeasts at nucleosome occupied regions and nucleosome depleted regions. The binding sites at nucleosome occupied regions exhibited a consistently higher evolution rate than those at nucleosome depleted regions, corroborating the difference in the selection constraints at the two regions. Finally, through site-directed mutagenesis experiment, we found that binding site gain or loss events at nucleosome depleted regions may cause more expression differences than those in nucleosome occupied regions.

Conclusions
Our study indicates the existence of different selection constraint on binding sites at nucleosome occupied regions than at the nucleosome depleted regions. We found that the binding sites have a different rate of evolution at nucleosome occupied and depleted regions. Finally, using transcription factor binding site-directed mutagenesis experiment, we confirmed the difference in the impact of binding site changes on expression at these regions. Thus, our work demonstrates the importance of composite analysis of chromatin and transcriptional evolution.
The mitochondrial genome sequence of the ciliate Paramecium caudatum reveals a shift in nucleotide composition and codon usage within the genus Paramecium
Authors: Barth Dana , Berendonk Thomas U 
Published: May 2011

Abstract
Background
Despite the fact that the organization of the ciliate mitochondrial genome is exceptional, only few ciliate mitochondrial genomes have been sequenced until today. All ciliate mitochondrial genomes are linear. They are 40 kb to 47 kb long and contain some 50 tightly packed genes without introns. Earlier studies documented that the mitochondrial guanine + cytosine contents are very different between Paramecium tetraurelia and all studied Tetrahymena species. This raises the question of whether the high mitochondrial G+C content observed in P. tetraurelia is a characteristic property of Paramecium mtDNA, or whether it is an exception of the ciliate mitochondrial genomes known so far. To test this question, we determined the mitochondrial genome sequence of Paramecium caudatum and compared the gene content and sequence properties to the closely related P. tetraurelia.

Results
The guanine + cytosine content of the P. caudatum mitochondrial genome was significantly lower than that of P. tetraurelia (22.4% vs. 41.2%). This difference in the mitochondrial nucleotide composition was accompanied by significantly different codon usage patterns in both species, i.e. within P. caudatum clearly A/T ending codons dominated, whereas for P. tetraurelia the synonymous codons were more balanced with a higher number of G/C ending codons. Further analyses indicated that the nucleotide composition of most members of the genus Paramecium resembles that of P. caudatum and that the shift observed in P. tetraurelia is restricted to the P. aurelia species complex.

Conclusions
Surprisingly, the codon usage bias in the P. caudatum mitochondrial genome, exemplified by the effective number of codons, is more similar to the distantly related T. pyriformis and other single-celled eukaryotes such as Chlamydomonas, than to the closely related P. tetraurelia. These differences in base composition and codon usage bias were, however, not reflected in the amino acid composition. Most probably, the observed picture is best explained by a hitherto unknown (neutral or adaptive) mechanism that increased the guanine + cytosine content in P. tetraurelia mtDNA on the one hand, and strong purifying selection on the ancestral amino acid composition on the other hand. These contradicting forces are counterbalanced by a considerably altered codon usage pattern.
In vitro interactions of Candida parapsilosis wild type and lipase deficient mutants with human monocyte derived dendritic cells
Authors: Nagy István , Filkor Kata , Németh Tibor , Hamari Zsuzsanna , Vágvölgyi Csaba , Gácser Attila 
Published: May 2011

Abstract

Background

Candida parapsilosis typically is a commensal of human skin. However, when host immune defense is compromised or the normal microflora balance is disrupted, C. parapsilosis transforms itself into an opportunistic pathogen. Candida-derived lipase has been identified as potential virulence factor. Even though cellular components of the innate immune response, such as dendritic cells, represent the first line of defense against invading pathogens, little is known about the interaction of these cells with invading C. parapsilosis. Thus, the aim of our study was to assess the function of dendritic cells in fighting C. parapsilosis and to determine the role that C. parapsilosis-derived lipase plays in the interaction with dendritic cells.

Results
Monocyte-derived immature and mature dendritic cells (iDCs and mDCs, respectively) co-cultured with live wild type or lipase deficient C. parapsilosis strains were studied to determine the phagocytic capacity and killing efficiency of host cells. We determined that both iDCs and mDCs efficiently phagocytosed and killed C. parapsilosis, furthermore our results show that the phagocytic and fungicidal activities of both iDCs and mDCs are more potent for lipase deficient compared to wild type yeast cells. In addition, the lipase deficient C. parapsilosis cells induce higher gene expression and protein secretion of proinflammatory cytokines and chemokines in both DC types relative to the effect of co-culture with wild type yeast cells.

Conclusions
Our results show that DCs are activated by exposure to C. parapsilosis, as shown by increased phagocytosis, killing and proinflammatory protein secretion. Moreover, these data strongly suggest that C. parapsilosis derived lipase has a protective role during yeast:DC interactions, since lipase production in wt yeast cells decreased the phagocytic capacity and killing efficiency of host cells and downregulated the expression of host effector molecules.
Optimizing the diagnostic power with gastric emptying scintigraphy at multiple time points
Authors: Hou Qingjiang , Lin Zhiyue , Dusing Reginald , Gajewski Byron J , McCallum Richard W , Mayo Matthew S 
Published: May 2011

Abstract

Background
Gastric Emptying Scintigraphy (GES) at intervals over 4 hours after a standardized radio-labeled meal is commonly regarded as the gold standard for diagnosing gastroparesis. The objectives of this study were: 1) to investigate the best time point and the best combination of multiple time points for diagnosing gastroparesis with repeated GES measures, and 2) to contrast and cross-validate Fisher's Linear Discriminant Analysis (LDA), a rank based Distribution Free (DF) approach, and the Classification And Regression Tree (CART) model.

Methods
A total of 320 patients with GES measures at 1, 2, 3, and 4 hour (h) after a standard meal using a standardized method were retrospectively collected. Area under the Receiver Operating Characteristic (ROC) curve and the rate of false classification through jackknife cross-validation were used for model comparison.

Results
Due to strong correlation and an abnormality in data distribution, no substantial improvement in diagnostic power was found with the best linear combination by LDA approach even with data transformation. With DF method, the linear combination of 4-h and 3-h increased the Area Under the Curve (AUC) and decreased the number of false classifications (0.87; 15.0%) over individual time points (0.83, 0.82; 15.6%, 25.3%, for 4-h and 3-h, respectively) at a higher sensitivity level (sensitivity = 0.9). The CART model using 4 hourly GES measurements along with patient's age was the most accurate diagnostic tool (AUC = 0.88, false classification = 13.8%). Patients having a 4-h gastric retention value >10% were 5 times more likely to have gastroparesis (179/207 = 86.5%) than those with ≤10% (18/113 = 15.9%).

Conclusions
With a mixed group of patients either referred with suspected gastroparesis or investigated for other reasons, the CART model is more robust than the LDA and DF approaches, capable of accommodating covariate effects and can be generalized for cross institutional applications, but could be unstable if sample size is limited.
Novel variants in the PRDX6 Gene and the risk of Acute Lung Injury following major trauma
Authors: Rushefski Melanie , Aplenc Richard , Meyer Nuala , Li Mingyao , Feng Rui , Lanken Paul N , Gallop Robert , Bellamy Scarlett , Localio A Russell , Feinstein Sheldon I , Fisher Aron B , Albelda Steven M , Christie Jason D 
Published: May 2011

Abstract

Background
Peroxiredoxin 6 (PRDX6) is involved in redox regulation of the cell and is thought to be protective against oxidant injury. Little is known about genetic variation within the PRDX6 gene and its association with acute lung injury (ALI). In this study we sequenced the PRDX6 gene to uncover common variants, and tested association with ALI following major trauma.

Methods
To examine the extent of variation in the PRDX6 gene, we performed direct sequencing of the 5' UTR, exons, introns and the 3' UTR in 25 African American cases and controls and 23 European American cases and controls (selected from a cohort study of major trauma), which uncovered 80 SNPs. In silico modeling was performed using Patrocles and Transcriptional Element Search System (TESS). Thirty seven novel and tagging SNPs were tested for association with ALI compared with ICU at-risk controls who did not develop ALI in a cohort study of 259 African American and 254 European American subjects that had been admitted to the ICU with major trauma.

Results
Resequencing of critically ill subjects demonstrated 43 novel SNPs not previously reported. Coding regions demonstrated no detectable variation, indicating conservation of the protein. Block haplotype analyses reveal that recombination rates within the gene seem low in both Caucasians and African Americans. Several novel SNPs appeared to have the potential for functional consequence using in silico modeling. Chi2 analysis of ALI incidence and genotype showed no significant association between the SNPs in this study and ALI. Haplotype analysis did not reveal any association beyond single SNP analyses.

Conclusions
This study revealed novel SNPs within the PRDX6 gene and its 5' and 3' flanking regions via direct sequencing. There was no association found between these SNPs and ALI, possibly due to a low sample size, which was limited to detection of relative risks of 1.93 and above. Future studies may focus on the role of PRDX6 genetic variation in other diseases, where oxidative stress is suspected.
Development of an ICF-based eligibility procedure for education in Switzerland
Authors: Hollenweger Judith 
Published: May 2011

AbstractStarting in January 2011, Switzerland will implement a multidimensional, context-sensitive procedure to establish eligibility in education systems. This paper provides a brief overview of the different eligibility-related practices with a special focus on children with disabilities. The paper then outlines the philosophical and conceptual framework of the eligibility procedure based on the International Classification of Functioning, Disability and Health, and the UN Convention on the Rights of Persons with Disability. The different components and methodology applied to organise information in the process towards establishing eligibility are also presented. Finally, some observations are made regarding transparent and just applications of the eligibility procedure, and the implementation of this new eligibility procedure.
Use of imaging biomarkers to assess perfusion and glucose metabolism in the skeletal muscle of dystrophic mice
Authors: Ahmad Nabeel , Welch Ian , Grange Robert , Hadway Jennifer , Dhanvantari Savita , Hill David , Lee Ting-Yim , Hoffman Lisa M 
Published: June 2011

AbstractBackgroundDuchenne muscular dystrophy (DMD) is a severe neuromuscular disease that affects 1 in 3500 boys. The disease is characterized by progressive muscle degeneration that results from mutations in or loss of the cytoskeletal protein, dystrophin, from the glycoprotein membrane complex, thus increasing the susceptibility of contractile muscle to injury. To date, disease progression is typically assessed using invasive techniques such as muscle biopsies, and while there are recent reports of the use of magnetic resonance, ultrasound and optical imaging technologies to address the issue of disease progression and monitoring therapeutic intervention in dystrophic mice, our study aims to validate the use of imaging biomarkers (muscle perfusion and metabolism) in a longitudinal assessment of skeletal muscle degeneration/regeneration in two murine models of muscular dystrophy.MethodsWild-type (w.t.) and dystrophic mice (weakly-affected mdx mice that are characterized by a point mutation in dystrophin; severely-affected mdx:utrn-/- (udx) mice that lack functional dystrophin and are null for utrophin) were exercised three times a week for 30 minutes. To follow the progression of DMD, accumulation of18F-FDG, a measure of glucose metabolism, in both wild-type and affected mice was measured with a small animal PET scanner (GE eXplore Vista). To assess changes in blood flow and blood volume in the hind limb skeletal muscle, mice were injected intravenously with a CT contrast agent, and imaged with a small animal CT scanner (GE eXplore Ultra).ResultsIn hind limb skeletal muscle of both weakly-affected mdx mice and in severely-affected udx mice, we demonstrate an early, transient increase in both18F-FDG uptake, and in blood flow and blood volume. Histological analysis of H&E-stained tissue collected from parallel littermates demonstrates the presence of both inflammatory infiltrate and centrally-located nuclei, a classic hallmark of myofibrillar regeneration. In both groups of affected mice, the early transient response was succeeded by a progressive decline in muscle perfusion and metabolism; this was also evidenced histologically.ConclusionsThe present study demonstrates the utility of non-invasive imaging biomarkers in characterizing muscle degeneration/regeneration in murine models of DMD. These techniques may now provide a promising alternative for assessing both disease progression and the efficacy of new therapeutic treatments in patients.
Immunocytochemical characterisation of cultures of human bladder mucosal cells
Authors: Woodman Jacqueline R , Mansfield Kylie J , Lazzaro Vittoria A , Lynch William , Burcher Elizabeth , Moore Kate H 
Published: May 2011

Abstract

Background
The functional role of the bladder urothelium has been the focus of much recent research. The bladder mucosa contains two significant cell types: urothelial cells that line the bladder lumen and suburothelial interstitial cells or myofibroblasts. The aims of this study were to culture these cell populations from human bladder biopsies and to perform immunocytochemical characterisation.

Methods
Primary cell cultures were established from human bladder biopsies (n = 10). Individual populations of urothelial and myofibroblast-like cells were isolated using magnetic activated cell separation (MACS). Cells were slow growing, needing 3 to 5 weeks to attain confluence.

Results
Cytokeratin 20 positive cells (umbrella cells) were isolated at primary culture and also from patients' bladder washings but these did not proliferate. In primary culture, proliferating cells demonstrated positive immunocytochemical staining to cytokeratin markers (AE1/AE3 and A0575) as well fibroblasts (5B5) and smooth muscle (αSMA) markers. An unexpected finding was that populations of presumptive urothelial and myofibroblast-like cells, isolated using the MACS beads, stained for similar markers. In contrast, staining for cytokeratins and fibroblast or smooth muscle markers was not co-localised in full thickness bladder sections.

Conclusions
Our results suggest that, in culture, bladder mucosal cells may undergo differentiation into a myoepithelial cell phenotype indicating that urothelial cells have the capacity to respond to environmental changes. This may be important pathologically but also suggests that studies of the physiological function of these cells in culture may not give a reliable indicator of human physiology.